Long-term outcome and prognostic factors in a patient cohort surgically treated for peritoneal metastasis from colorectal cancer and pseudomyxoma peritonei

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Long-term outcome and prognostic factors in a patient cohort surgically

treated for peritoneal metastasis from colorectal cancer and

pseudomyxoma peritonei

Line Kyllingstad

Project thesis at the Faculty of Medicine UNIVERSITY OF OSLO

2018

Supervisor: Kjersti Flatmark - Professor II - Department of

Gastroenterological Surgery, Oslo University Hospital, University of Oslo Co-supervisor: Ida S. Frøysnes – PhD student, University of Oslo.

Research fellow, the Norwegian Cancer Society

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Long-term outcome and prognostic factors in a patient cohort surgically treated for

peritoneal metastasis from colorectal cancer and pseudomyxoma peritonei

Fig. 1 – The peritoneal cavity (illustration) from Oncolex [1])

Title: Long-term outcome and prognostic factors in a patient cohort surgically treated for peritoneal metastasis from colorectal cancer and pseudomyxoma peritonei

Author: Line Kyllingstad http://www.duo.uio.no/

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Abstract

Background: Peritoneal metastasis from colorectal cancer (PM-CRC) and pseudomyxoma peritonei (PMP) are conditions with a historically poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may offer treatment in selected patients with intraperitoneal malignancies, but the procedure is associated with morbidity and mortality, and improving the treatment and selection criteria for patients is an important task. The Norwegian Radium Hospital, Oslo University Hospital is the national treatment center for CRS-HIPEC in Norway. This project thesis aims to analyze long-term outcome and prognostic factors in a cohort of patients where tumor samples have been collected for further molecular analyses.

Patients and methods: 122 PM-CRC patients and 77 PMP patients were included in the cohort. Patient characteristics and survival was obtained from an institutional database and by retrospectively studying patient charts. Long-term outcome and potential prognostic factors were examined using survival analysis.

Results: For PM-CRC patients undergoing CRS-HIPEC the five-year overall survival (OS) was 36 % and the estimated median OS was 42 months with a median follow-up time of 32 months. Estimated median disease-free survival (DFS) was 11 months, with 18 months median follow-up. In the surgery only group estimated median OS was 16 months, with a median follow-up of 40 months. Peritoneal cancer index (PCI) was associated with OS in univariable analysis with HR 1.06 (1.01-1.12) for every increase in PCI-score (P=0.02). For PMP patients undergoing CRS-HIPEC the five- and ten-year OS were 88% and 73%,

respectively, with 51 months median follow-up. For the surgery only group, five- and ten year OS were 0%, estimated OS was 27 months, with a median follow-up of 39 months.

Histopathological differentiation, PCI and female gender were associated with OS in univariable analysis in the PMP patients treated with CRS-HIPEC.

Conclusions: Patients with PM-CRC and PMP treated with CRS-HIPEC achieved

satisfactory long-term outcome in accordance with results from previous reports. Patients in the surgery only group had a much less favorable outcome. PCI was the only prognostic factor significantly associated with OS in PM-CRC patients treated with CRS-HIPEC. The strongest prognostic factors in PMP patients treated with CRS-HIPEC were PCI and histopathological differentiation.

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IV

Acknowledgements

First I would like to express my gratitude to my supervisor Kjersti Flatmark for giving me the opportunity to write this project thesis under her supervision. I am thankful that she let me be a part of her research group from when I first started on the project thesis, helping me to increasingly understand this complex research field and to get to know many great colleagues that I have learned so much from. Kjersti has taught me a lot about the creative process of writing scientific manuscripts and all the steps in the process leading up to the results in research. She has been a supportive and motivating supervisor, closely supervising the writing process and always finding time to discuss questions despite a busy schedule.

Secondly a huge thanks to co-supervisor Ida Storhaug Frøysnes for all the time and effort she have put into helping me with the project thesis, with SPSS and statistics, to sort out

pathology report answers, proofreading and much more. I would also like to thank Annette Torgunrud Kristensen and Christin Lund-Andersen who have helped me and taught me about molecular analyses and bioinformatics.

The work presented in this project thesis has emerged from the peritoneal metastasis project at the Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital. I would like to acknowledge the employees involved both on the clinical and translational research side, and last but not least the patients taking part in this research project.

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1 Introduction

The Norwegian Radium Hospital (Oslo University Hospital) is the national treatment center for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in Norway. This highly specialized treatment involves the surgical removal of all visible intraperitoneal tumor deposits and heated intraabdominal chemotherapy lavage performed immediately after completion of surgery. The method was developed in the 1980-and 1990s [2] and was initially used for patients with the rare malignancy pseudomyxoma peritonei (PMP). From 1994 CRS and intraabdominal chemotherapy was performed in patients with PMP at the Norwegian Radium Hospital, and today also eligible patients with abdominal mesothelioma and peritoneal metastasis from colorectal cancer (PM-CRC) patients are included. However, the treatment is associated with morbidity and mortality and many patients experience disease recurrence, illustrating the need for better treatment and selection criteria. In this study I will investigate long-term outcome and prognostic factors in a cohort of patients with PM-CRC or PMP surgically treated at this center between 2004 and 2015.

1.1 Peritoneal metastasis from colorectal cancer

Colorectal cancer (CRC) is the second and third most common cancer in women and men respectively, in Norway [3] and worldwide [4]. Peritoneal metastasis (PM) is not an uncommon mode of disease progression from CRC. One study found synchronous or metachronous PM in 13 % of a group of approximately 3000 patients with CRC [5]. The prognosis after being diagnosed with PM-CRC has historically been very poor, with a median overall survival (OS) of less than 7 months [6, 7]. However, for a group of patients with resectable disease limited to the peritoneal cavity, the introduction of CRS-HIPEC has given these patients a possibility of long-term survival and in some cases a possibility for cure. This treatment has been shown to improve the survival in one randomized controlled trial [8], a limited number of case-control studies [9-11] and several cohort studies [12]. A recently published cohort study from our national treatment center reported an estimated median OS of 47 months in patients treated with CRS-HIPEC [13].

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1.2 Pseudomyxoma peritonei

PMP is a rare, slow-growing malignancy with the disease usually limited to the peritoneal cavity [14], which made it a model disease for development of the CRS-HIPEC technique. It most commonly arises from appendiceal neoplasms [15]. PMP can be defined as the

intraperitoneal accumulation of mucus due to mucinous neoplasia characterized by the redistribution phenomenon, meaning large tumor volumes will be found at some

predetermined anatomic sites in the peritoneal cavity [16]. It can include mucinous ascites, peritoneal implants, omental cake and ovarian involvement. The terminology and

classification of PMP and the primary mucinous appendiceal neoplasms has been debated in the literature over several years, with different systems for histological classification co- existing and overlapping [17]. Until recently, PMP tissue samples in our cohort were classified into three histopathological subgroups; disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis with intermediate features (PMCA-I) and peritoneal mucinous carcinomatosis (PMCA) according to the criteria described by Ronnett et al [18]. From 2016, a new consensus classification system was introduced which divides the peritoneal component of the disease into four subgroups; “Acellular mucin”, “Low-grade mucinous carcinoma peritonei or DPAM”, High-grade mucinous carcinoma peritonei or PMCA” and “High-grade mucinous carcinoma peritonei with signet ring cells or PMCA-S) as described in Table 1 [15]. In this project thesis the three and four subgroups have been

regrouped in to two main categories for analytical purposes: “Acellular mucin” and “DPAM”

are designated low-grade, and “PMCA-I”, “PMCA” and “PMCA-S” as high-grade.

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3 Table 1. Classification of the peritoneal component of PMP by Carr et. al

The prognosis for PMP patients is far better than for PM-CRC, with a median OS for patients undergoing CRS-HIPEC reported at 196 months (16,3 years) [19]. However, the prognosis for PMP may vary depending on the histopathological subtype. A study from our national treatment center found that histopathological differentiation was the most important

prognostic factor for overall survival, with 5-and 10-year OS of 88% and 86% in the DPAM- group, 67% and 42 % in the PMCA-I-group and 58% and 38% in the PMCA-group [20].

1.3 Aim of the project thesis

Even though CRS-HIPEC has greatly improved prognosis for both PMP and PM-CRC, the treatment is associated with morbidity and mortality and many patients do not benefit from it.

Improvement of treatment and patient selection criteria are therefore important research goals in this field, and this project thesis has emerged as a part of a larger study aiming for the above. The larger study, “Peritoneal surface malignancies – characterization, models and treatment strategies” is part of a collaborative translational research project at the Department

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of Tumor Biology and Department of Gastroenterological Surgery at the Norwegian Radium Hospital/Oslo University Hospital. Since 2004, tumor tissue samples from consenting patients undergoing treatment for peritoneal metastasis at the Norwegian Radium Hospital have been collected and stored in a research biobank. One aim of the study is to analyze these tissue samples to detect genomic drivers in the tumor cells such as genetic mutations, copy number variations and investigate expressed downstream effects on RNA and protein levels. The purpose of this project thesis is to examine and present clinical data of the patient cohort included in the molecular analyses.

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2 Patients and methods

2.1 Patient population

Patients surgically treated for peritoneal metastasis with CRS-HIPEC in the period 2004 to 2015 were prospectively registered in our institutional database for peritoneal malignancies, where information regarding clinicopathological data, treatment and outcome were recorded.

The study was approved by the Regional Committee for medical and health research ethics South-East Norway (2010/2390 s-07160b) and written informed consent from patients was obtained. As the main study that this project thesis is derived from will look at molecular analysis of tumor cells, only patients with tumor samples in the biobank were included in this cohort (n=199). The known difference in prognosis and survival between PM-CRC and PMP led us to divide the group by histopathological classification, into a PM-CRC (n=122) and a PMP-group (n=77). For the PM-CRC group we have included patients treated for PM-CRC, including two patients with primary tumor in the small bowel. For the second group we have included patients treated for PMP of appendiceal origin or strongly suspected appendiceal origin in the case of previously removed appendix. One patient included in the PMP group had urachus as the origin of primary tumor. One patient where the origin of the primary tumor was unknown was excluded. Another patient with no verified peritoneal metastasis during surgery was also excluded. Information regarding disease recurrence was obtained by retrieving patient records and radiological work-up from referring hospitals where patients received postoperative follow-up. Recurrence was defined as detection of local recurrence of peritoneal disease or lymph node/other organ metastasis. Detection of both local recurrence and lymph node or organ metastasis within three months was considered synchronous recurrence. Survival data was obtained from the Norwegian National Registry on June 19, 2017, and patients alive at this date were censored. Follow-up time was calculated using the Reversed Kaplan-Meier method

2.1.1 PM-CRC

122 patients treated between 2004 and 2015 with tumor samples in the peritoneal metastasis biobank were identified in the PM-CRC group. In 43 patients the complete CRS-HIPEC

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procedure was not performed for the following reasons: unresectable disease (n=42), postoperative complications (n=1). In 79 patients CRS-HIPEC was performed.

2.1.2 PMP

77 patients treated between 2004 and 2015 with tumor samples were identified from the peritoneal metastasis biobank in the PMP group. In 15 patients the complete CRS-HIPEC procedure was not performed for the following reasons: unresectable disease (n=14), lymph node metastasis (n=1). In 62 patients CRS-HIPEC was performed.

2.2 Treatment

CRS involving perinectomy procedures, and organ resections as necessary, was performed with the intention to remove all visible tumor [21]. Residual tumor after CRS was evaluated using the Completeness of Cytoreduction (CC) score: CC-0, no tumor, CC-1 tumor <2,5 mm, CC-2, tumor 2,5-25 mm, CC-3, tumor >25 mm. [22]. HIPEC with mitomycin C (35 mg/m2) (maximum 70 mg/m2) was administered to patients where complete cytoreduction (CC-0, CC-1) was achieved. The background for this patient/treatment selection is that the

chemotherapy is thought to diffuse 2-3 mm into the tissue, and therefore only patients with complete cytoreduction will benefit from the treatment. For the administration of

chemotherapy the open Coliseum technique was used until 2008. From 2008 a closed

technique with open abdomen was used [23]. For patients where complete cytoreduction was not achieved, the surgery was regarded as a debulking or explorative procedure (N=51). One patient achieved complete cytoreduction but did not receive intraperitoneal chemotherapy due to postoperative complications. Another patient underwent a complete CRS procedure but due to verified lymph node metastasis, intraperitoneal chemotherapy was not administered. The above patients were classified in the surgery only group. For the majority of patients in the CRS-HIPEC group (n=146) CRS and HIPEC were performed in the same procedure (135 of 146).

2.3 Assessment of peritoneal tumor distribution

Tumor distribution found during surgery was prospectively registered using the peritoneal cancer index (PCI) of Sugarbaker [22]. This scoring tool divides the abdominal cavity into

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7 nine regions, and the small bowel into four, adding up to a total of thirteen regions. Each region is given a score from 0-3 based on the size of tumor. The sum of these regions makes up the Peritoneal Carcinomatosis Index (PCI) ranging from 0-39.

Fig. 2 – Peritoneal cancer index (PCI) scoring tool by Sugarbaker [22].

2.4 Primary tumor localization and histopathological evaluation

In both groups information regarding the localization of the primary tumor was obtained from the institutional database. In some PMP patients where the appendix was previously removed and discarded without histopathological examination, we assumed a probable appendiceal origin. For the PMP patients histopathological data of the peritoneal component of the disease were classified into two histopathological subgroups, low-grade and high grade, as described in the introduction chapter.

2.5 Statistical analysis

Categorical variables were described using frequencies/percentages and continuous variables were described with median/min-max. Univariable analysis was performed using Cox

regression analysis or the Kaplan-Meier method, with survival time from date of surgery to

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death or censoring date June 19^th 2017 (overall survival (OS)) and from date of CRS-HIPEC to the time of recurrence (peritoneal relapse and/or distant metastasis, new primary cancer, death or last follow-up (disease-free survival (DFS)). The log-rank test was used to compare differences in survival.

In the case of patients with multiple surgical procedures, we selected the date of CRS-HIPEC as the starting point for survival analysis in the patient group undergoing CRS-HIPEC. For patients in the surgery only group, the date of the first surgical procedure in our institution was chosen.

Statistical analyses were conducted using SPSS Software (version 23.0 SPSS Inc., Chicago, IL). P-values <0.05 were considered statistically significant.

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3 Results

3.1 PM-CRC - Patient characteristics and outcome

Table 2 summarizes clinicopathological characteristics of the 122 PM-CRC patients, stratified according to treatment. Seventy-nine patients were treated with CRS-HIPEC, comprising 51 women (65%) and 28 men (35%), where median age was 58 years (22-77). Forty-three patients were treated with surgery only, comprising 26 women (60%) and 17 men (40%), median age was 59 years (36-74). Median PCI was 11 (2-26) in the CRS-HIPEC group and 27 (8-39) in the surgery only group. Colon was the most common localization for the primary tumor in both the CRS-HIPEC group (n=63) and the surgery only group (n=35). In the CRS- HIPEC group, 50 patients (63%) experienced disease recurrence; with PM only (n=19), PM and distant metastasis (n=16) and distant metastasis only (n=15) as the first site of recurrence.

Thirty-two patients (41%) died within the follow-up period in the CRS-HIPEC group, and 38 (88%) in the surgery only group.

Table 2 - Patient characteristics for the PM-CRC patients, stratified according to treatment

Variable CRS-HIPEC Surgery only

N (%) N (%)

Patients 79 (100) 43 (100)

Median age, years (min-max) 58 (22-77) 59 (36-74)

Gender

Female 51 (65) 26 (60)

Male 28 (35) 17 (40)

PCI

0-10 37 (47) 4 (9)

11-20 30 (38) 5 (12)

21-39 12 (15) 34 (79)

Primary tumor localization

Appendix 8 (10) 5 (12)

Colon 63 (80) 35 (81)

Rectum 6 (8) 3 (7)

Small bowel 2 (3) 0

Outcome

Overall mortality 32 (41) 38 (88)

First recurrence

No recurrence 29 (37)

PM only 19 (24)

PM and distant metastasis 16 (20)

Distant metastasis only 15 (19)

*CRC –colorectal cancer; CRS, cytoreductive surgery, DFS disease-free survival, HIPEC, hyperthermic intraperitoneal chemotherapy, OS, overall survival, PCI, peritoneal cancer index, PM, peritoneal metastasis

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Table 3 and 4 summarizes survival analyses. The estimated 3-and 5-year OS were 58 % and 36 %, respectively, and estimated median OS was 42 months (95% CI 34-50) in the CRS- HIPEC group. Median follow-up was 32 months (95% CI 28-35). In the surgery only group estimated 3- and 5 year OS were 10% and 0 % respectively, and estimated median OS was 16 months (95% CI 14-19), with median follow-up of 40 months. In the CRS-HIPEC group the estimated median DFS was 11 months (95% CI 6-15), with a median follow-up time of 18 months (95% CI 11-26). PCI, when stratified into the groups of 0-10, 11-20 and > 20, did not show any statistically significant association with OS or DFS using the Kaplan-Meier method.

PCI did however show a statistically significant association with survival using univariable Cox regression analysis, where PCI was investigated as a continuous variable; with a hazard ratio of 1.06 (95% CI 1.01-1.12) for prediction of OS (p=0.02). This means that for every increase in PCI, the risk of death increased with 6%. For DFS the hazard ratio for PCI was 1.04 (95% CI 1.00-1.08), p=0.06.

Table 3 –Univariable analysis of OS and DFS in the PM-CRC patients Variable

No. of patients

OS 5-year

(%) OS (95%CI) P DFS (95%CI) p

Surgery only 43 0 16 (14-19) NA

CRS-HIPEC 79 36 42 (34-50) 11 (6-15)

Gender 0.7 0,5

Female 51 41 41 (32-51) 10 (5-16)

Male 28 26 43 (41-45) 12 (6-19)

PCI 0.2 0,09

0-10^a 37 55 - 17 (8-26)

11-20 30 22 42 (21-64) 10 (7-12)

21-39 12 35 43 (17-68) 14 (7-16)

* Median OS and DFS are expressed in months. CRC –colorectal cancer; CRS, cytoreductive surgery, DFS disease-free survival, HIPEC, hyperthermic intraperitoneal chemotherapy, NA, not applicable, OS, overall survival, PCI, peritoneal cancer index, PM, peritoneal metastasis

aMedian OS not reached

Table 4 – Cox-regression analysis of survival after CRS-HIPEC in the PM-CRC group

OS DFS

HR (95%CI) P HR (95%CI) P

PCI continuous variable 1.06 (1.01-1.12) 0.02 1.04 (1.00-1.08) 0.06

*CRC –colorectal cancer; CRS, cytoreductive surgery, DFS disease-free survival, HIPEC, hyperthermic intraperitoneal chemotherapy, HR, Hazard ratio, OS, overall survival, PCI, peritoneal cancer index, PM, peritoneal metastasis

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Fig. 3. Survival curves after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal metastases from colorectal cancer (PM-CRC) (a) Overall survival (OS) and disease-free survival (DFS) (b) Peritoneal cancer index (PCI) and OS.

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3.2 PMP - patients characteristics and outcome

Table 5 summarizes clinicopathological characteristics of the PMP-patients, stratified according to treatment. Sixty-two patients were treated with CRS-HIPEC, comprising 36 women (58%) and 26 men (42%), median age was 56 years (27-78). Fifteen patients were treated with surgery only, comprising 12 women (80%) and 3 men (20%). Median age in the surgery only group was 64 years (38-82). Median PCI was 22 (3-39) in the CRS-HIPEC group and 35 (14-39) in the surgery-only group. With the exception of one case with urachus as the primary site, all cases had verified (n=71) or probable (n=5) appendiceal origin.

Histopathological classification in the CRS-HIPEC group showed low grade histology in 48 patients (77%) and high grade in 14 (23%). In the surgery only group histopathological classification showed low grade in 9 patients (60%) and high grade in 6 (40%). In the CRS- HIPEC group, 17 patients (27%) experienced disease recurrence; with PM only (n=15) and PM and distant metastasis (n=2) as the first registered recurrence. Eight patients (13%) died within the follow-up period in the CRS-HIPEC group, and 9 (60%) in the surgery only group.

Table 5 - Patient characteristics for the PMP patients, stratified according to treatment

CRS-HIPEC Surgery only

N (%) N (%)

Patients 62 (100) 15 (100)

Median age, years (min-max) 56 (27-78) 64 (38-82)

Gender

Female 36 (58) 12 (80)

Male 26 (42) 3 (20)

PCI

0-10 8 (13) 0 (0)

11-20 18 (29) 2 (13)

21-30 15 (24) 3 (20)

31-39 21 (34) 10 (67)

Primary tumor Localization

Appendix 58 (94) 13 (87)

Probably appendix 3 (5) 2 (13)

Urachus 1 (2) 0 (0)

Histopathological differentiation

Low grade 48 (77) 9 (60)

High grade 14 (23) 6 (40)

Outcome

Overall mortality 9 (15) 9 (60)

First recurrence

No recurrence 45 (73)

PM only 15 (24)

PM and distant metastasis 2 (3)

Distant metastasis only 0 (0)

*CRS, cytoreductive surgery, DFS disease-free survival, HIPEC, hyperthermic intraperitoneal chemotherapy, OS, overall survival, PCI, peritoneal cancer index, PM, peritoneal metastasis, PMP- pseudomyxoma peritonei

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13 Table 6 summarizes survival data. For the group receiving CRS-HIPEC, the estimated 5-and 10-year OS were 88% and 73%, respectively, with a follow-up time of 51 months (95%CI 38- 64). Median follow-up time was 25 months (95% CI 17-33) for DFS. Estimated median OS and estimated median DFS was not reached in the CRS-HIPEC group, because of a low mortality and recurrence rate within the follow-up period. In the surgery only group, the estimated 5-year and 10-year OS were 0%, estimated median OS was 27 months (95% CI 7- 47), with a median follow-up time of 39 months (95% CI 17-61). Univariable analyses using the Kaplan Meier method in the CRS-HIPEC group showed statistically significant

association between OS and histopathological subtype (p=0.01), PCI when stratified in to the groups 0-10, 11-20, 21-30 and >30 (p=0.02) and gender (p=0.02).

Table 6 – survival data and univariable analysis of OS in the PMP group

No. of patients OS (%) P

Variable 5-year 10-year

Surgery Only 15 0 0

CRS-HIPEC 62 88 73

Gender 0.02

Female 36 91 91

Male 25 83 49

PCI 0.02

0-10 7 100 100

11-20 18 94 94

21-30 15 92 92

31-39 21 76 21

Histopathological classification 0.01

Low grade 48 90 90

High grade 14 78 46

*CRS, cytoreductive surgery, HIPEC, hyperthermic intraperitoneal chemotherapy, OS, overall survival, PCI, peritoneal cancer index, PM, peritoneal metastasis, PMP, pseudomyxoma peritonei

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Fig. 4. Overall survival (OS) and histopathological differentiation after cytoreductive surgery (CRC) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with pseudomyxoma peritonei (PMP)

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4 Discussion

This project thesis describes long-term outcome and associated prognostic factors for a selected group of patients in which tumor tissue samples were collected and stored in a biobank for molecular analyses. This method of selection differ somewhat from what is most common for cohort studies; consecutive patient series including all patients treated in a certain time period. By selecting patients based on availability of tumor samples, all PM-CRC and PMP patients at our institution were not included and we cannot exclude that there could be a potential selection bias. However, the present results are in line with previous cohort studies on PM-CRC and PMP from the same institution, supporting that our patient cohort is representative.

The survival analysis in this project thesis has mainly focused on the group undergoing CRS- HIPEC, implicitly having achieved complete cytoreduction. Patients (both PMP and PM- CRC) with too extensive disease to undergo CRS-HIPEC may not always be recognized by pre-operative work-up. This may lead to surgery where the aim or hope is to do CRS-HIPEC, but where the surgeons during assessment of peritoneal distribution or later recognize that complete cytoreduction is not achievable and the procedure is thus converted to explorative and/or debulking surgery. These patients may also have other comorbid factors that will affect their prognosis negatively. If these patients were included in survival analyses using an intention-to treat approach, the efficacy of CRS-HIPEC would be underestimated [20]. For this reason we have separated the CRS-HIPEC patients from the surgery only patients, and the difference in outcome is in line with what we expected, with a median OS of 42 months for CRS-HIPEC, vs. 16 months for surgery only (PM-CRC group). In the PMP group the five-year OS for the CRS-HIPEC was 88 %, vs 0% in the surgery only group.

In the PM-CRC group treated with CRS-HIPEC the five-year OS was 36 % with a median OS of 42 months, which is in line with results from a previous publication from our institution [13]. This previous publication included PM-CRC patients undergoing CRS-HIPEC, where 22 out of 119 patients overlap with our present PM-CRC CRS-HIPEC group (N=79). Other tertiary referral centers have reported similar OS [9, 12, 24]. This survival rate is considerably longer than for patients receiving contemporary systemic chemotherapy where a median OS of 17 months has been reported [11].

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Although CRS-HIPEC has improved outcome in PM-CRC, recurrence of disease will occur in approximately 50 % of the patients within the first year [25-27]. Estimated median DFS in our cohort was 11 months for PM-CRC patients undergoing CRS-HIPEC. This is also in line with previous reports [8, 13]. Despite the relatively short DFS, the improvement in OS remains high in patients who completed CRS-HIPEC. This supports that CRS-HIPEC can be beneficial to PM-CRC patients despite high recurrence rates.

Follow-up time for DFS was relatively short, with an estimated median of 18 months. This may affect the significance and reliability of these results. For OS follow-up time was considerably longer, with an estimated median follow-up of 32 months.

In our analyses of the PM-CRC group PCI was the only parameter associated with OS using Cox-regression analysis, and was also borderline significantly associated with DFS. However, when stratifying patients according to PCI, we saw a relatively similar OS (42 vs 43 months) and DFS (10 vs 14 months) in the PCI 11-20 group and PCI >20 group. Other studies have reported PCI as a prognostic factor in PM-CRC patients, and many centers have regarded PCI>20 as a relative contraindication to CRS-HIPEC for PM-CRC [25, 28, 29]. One study that found a linear correlation between PCI and OS has suggested PCI 12-17 and PCI>17 as relative and absolute contraindications [30]. Authors at our institution previously found that a cut-off value of PCI >12 corresponded to 100 % specificity for prediction of recurrence, and also points out that there is no difference in the long-term outcome for patients with PCI 11- 20 and PCI>20 [13], which is in line with the present study. Although the finding of

association between PCI and long-term outcome is in line with most of the literature in this field, the similar OS and DFS found in the PCI > 20 group is somewhat unexpected and has no obvious explanation. The PCI>20 group is however relatively small (n=12), and it is possible that the long survival of these patients could be related to a high prevalence of

favorable prognostic factors in the group, such as age, low comorbidity and good performance status, making them eligible for CRS-HIPEC despite a high PCI.

Another factor that could influence the PCI/survival association is the heterogeneity of the cancer types in the group, as we have included primary tumors from different locations in the intestine, including appendix and two cases of tumors in the distal ileum. Four out of twelve cases in the PCI>20 group were appendiceal primary tumors. It will be interesting to see the awaited molecular analyses, hoping that they can provide some more insight regarding

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17 variation in tumor biology and location in the intestine, and implications this may have on survival.

For the PMP CRS-HIPEC group, the estimated 5-and 10-year OS were 88% and 73 %, which is in line with published results from our institution [20] and others [19, 31]. Low-grade histopathological differentiation (p=0.01), low PCI when stratified into four groups (p=0.02), and female gender (p=0.02) were all found to be positively associated with OS in univariable analyses. Although the findings are in line with what we expected, the reliability of these findings is however of some uncertainty, as we only have uni- and not multivariable analyses.

It is possible that the factors confound each other. However, follow-up time in the PMP group was relatively long, with an estimated median of 51 months for OS and 25 months for DFS.

Histopathological differentiation has been regarded as the most important prognostic factor in patients with PMP treated with CRS-HIPEC [20, 32, 33]. Although the terminology and classification may vary in the literature, it is a common finding that disease with high-grade histologic features has a less favorable prognosis than disease with low-grade histologic features. Some therefore argue that in patients with a high-grade histopathology one should use a similar approach for surgery and apply PCI cut-off values as in PM-CRC [34]. Others have concluded that the acceptable OS found in the high grade group with PCI>20 should advocate that PCI>20 should not be used as an exclusion criterion for CRS-HIPEC [20, 35]

given that they present clinically with PMP and that complete CRS is achievable.

In this study, PCI when stratified into four groups was associated with OS (p=0.02) for the PMP group. However as noted above, this is not adjusted for histopathological differentiation.

A recent multi-center study looking at peritoneal dissemination from high-grade appendiceal primaries, found that PCI was not predictive of survival after CRS-HIPEC [36]. This is in contrast to our finding, but the results are not completely comparable as the patient groups are different regarding burden of high grade histological differentiation. The literature is divided when it comes to PCI as a prognostic factor in PMP, and although we find a significant association between PCI and OS in the present study, this must be interpreted with caution because of a small cohort (N=62) and for this reason, multivariable analysis was not performed.

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The observation of female gender as a factor positively associated with OS in PMP has been shown before [20, 34], and although it is an interesting observation we see no obvious explanation for this finding.

This present study has the limitations of a single-institutional cohort analysis, including potential selection bias, institutional learning curves, and to some extent retrospective data- collection. Although most data was prospectively registered in our database, some missing data had to be obtained from charts or remained missing. The extent of patient characteristics, outcome data and statistical analyses presented in the project thesis is limited. This is mostly due to the purpose being data collection for a molecular study, and the timeframe of the project thesis. Nonetheless, the overall results that have been presented correspond well with previously published studies from our institution on similar patient cohorts [13, 20].

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5 Conclusions

Patients with PM-CRC and PMP treated with CRS-HIPEC achieved satisfactory long-term outcome in accordance with results from previous reports. Patients in the surgery only group had a much less favorable outcome. PCI was the only prognostic factor significantly

associated with OS in PM-CRC patients treated with CRS-HIPEC. OS was considerably longer than DFS in the PM-CRC group. The strongest prognostic factors in PMP patients treated with CRS-HIPEC were PCI and histopathological differentiation. Further studies are needed to establish common selection criteria for CRS-HIPEC.

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