PERITONEAL SPREAD OF COLORECTAL CANCER: PREVENTION AND

TREATMENT

WP Ceelen, MD, PhD

Department of Gastrointestinal Surgery

Ghent University Hospital

De Pintelaan 185, B-9000 Ghent, Belgium

Wim.ceelen@ugent.be

Introduction

With an annual worldwide mortality rate of over half a million, colorectal cancer
(CRC) remains a major cause of cancer related mortality.1 Since malignant disease
ultimately causes death by distant organ invasion, the unravelling of molecular
mechanisms underlying hematogenous and lymphatic metastasis is a topic of
intensive research activity.2 In parallel, the introduction of targeted biological agents
has met with considerable survival prolongation in patients with metastatic disease.3
On the other hand, intraperitoneally located tumors may be at the origin of
locoregional peritoneal spread. Although often coexisting with systemic disease, it is
increasingly realised that colorectal tumor dissemination within the peritoneal cavity
may represent a separate phenotypic and molecular entity. Established carcinomatosis
from CRC is much less responsive to systemic therapy and causes considerable
morbidity in affected patients. Recognition of the causes and mechanisms of
peritoneal metastasis may contribute to strategies to effectively prevent the
development of PC in colorectal cancer. Moreover, in a small group of patients with
low volume peritoneal disease, a locoregional treatment strategy combining surgery
with intracavitary cytotoxic therapy has been shown to improve outcome.4

Incidence and Prognostic Significance of Peritoneal Tumor Spread from

Colorectal Cancer

Synchronous peritoneal metastases are found at the time of surgery with curative
intent in about five to six percent of patients, and are more frequently observed in
right sided cancers.5 Peritoneal carcinomatosis is present in 25-30% of patients with
recurrent or metastatic colorectal cancer; in approximately 3% isolated peritoneal
disease without systemic spread is observed.6, 7 The prognostic outlook of patients
with palliatively managed PC from colorectal malignancy is grim: the French
multicenter EVOCAPE 1 study found a median survival of 5.2 months.8 Systemic
chemotherapy improves survival in metastatic colorectal cancer, but the presence of
PC has been shown to be an adverse determinant of response and prognosis in patients
treated with fluorouracil or irinotecan based systemic chemotherapy.9-11 Contrary to
those with visceral metastasis, patients with PC are at risk of develop debilitating
symptoms such as obstruction and ascites formation, while the risk of perforation
induced by the VEGF inhibitor bevacizumab may be more pronounced.12
Although established peritoneal metastases are found in only a limited percentage of
patients undergoing surgery, it is likely that microscopic spread occurs much more
frequently.13 Several authors have studied the presence of free peritoneal cancer cells
immediately before or after colorectal cancer resection, and related their presence to
local recurrence and survival (Table 1). Overall, the results of these studies suggest
that microscopic peritoneal disease at the time of surgery represents a prognostic
factor and thus a possible therapeutic target in resectable CRC. A similar conclusion
was formulated by the authors of a recent meta-analysis showing that the presence of
free peritoneal cancer cells pre CRC resection was associated with a higher risk of
overall recurrence (Odds Ratio 0.19–0.88) and local recurrence (Odds Ratio 0.21–
0.82) while post resection, the presence of free cancer cells resulted in a significantly
higher risk of overall recurrence (Odds Ratio 0.03–0.18).14 In parallel, in vitro studies
and animal tumorigenicity assays have shown that exfoliated CRC cells have the
potential to proliferate and invade.15, 16
In many CRC patients, the occurrence of carcinomatosis is a late manifestation of
disseminated cancer. There is, however, a subset of patients in whom peritoneal
disease progression appears without any systemic spread. The prototypic syndrome in
this regard is pseudomyxoma peritonei (PMP), which was shown to originate from
mucinous neoplasms of the appendix and whose clinical course is characterized by
progressive panabdominal mucinous carcinomatosis without any systemic metastasis.
Bibi and coworkers recently demonstrated that a specific expression profile of
cadherins underlies the intriguing behaviour of PMP.17 Compared to adenocarcinoma
of the colon, PMP samples showed increased N-cadherin, reduced E-cadherin, and
increased vimentin expression, suggesting that the propensity for peritoneal spread is
caused by an epithelial to mesenchymal transition (EMT) state. Similarly, differences
in gene expression profile have been described between systemic (hepatic) and
isolated peritoneal metastases.18, 19 In a preliminary analysis, we compared gene
expression between CRC liver metastases and isolated peritoneal metastases, and
found 179 genes related to immune response, cellular differentiation, (EMT), and cell
growth to be differentially expressed.20 Pathway analysis showed that IL-6 and TGF-β
signalling were upregulated in peritoneal metastases. Taken together, these results
suggest that in some patients, peritoneal progression of CRC is driven by a specific
set of genetic alterations.

Mechanisms of Peritoneal Tumor Spread of Colorectal Cancer

The development of peritoneal carcinomatosis can be viewed as several well defined

steps.

1. Detachment of cells from the primary tumor

The first step in the cascade resulting in peritoneal carcinomatosis (PC) is liberation
of tumour cells from the primary cancer mass (Fig). This process can occur
spontaneously, or can be iatrogenically caused. First, downregulation of cell-cell
adhesion molecules, such as E-cadherin via the transcription factor TWIST, has been
reported to promote cancer cell detachment21, 22 Second, spontaneous shedding of
loose cells is facilitated by the elevated interstitial fluid pressure (IFP) in most solid
tumours.23 This hydrodynamic property of malignant tissue is caused by rapid cellular
proliferation, defective lymphatic drainage, fibrosis and contraction of the interstitial
matrix, and increased osmotic pressure generated by anaerobic glycolysis and leakage
of plasma proteins.24, 25 Several clinical studies showed a significantly poorer outcome
in CRC patients in whom visceral peritoneal invasion was identified (pT4a) on
pathological examination of the resection specimen (Tabel 2). Similarly, spontaneous
bowel perforation has been shown to represent an adverse prognostic event and to
more than double the risk of postoperative carcinomatosis compared to non perforated
cancers.26-29
Third, cancer cell spillage by inadvertent cutting into tumor tissue or by sectioning
draining blood, lymphatic, or biliary channels has been shown to promote
locoregional tumor dissemination.30, 31

2. Peritoneal transport

Free cancer cells in the peritoneal cavity are subject to passive movement dictated by
gravity and by the excursion of the diaphragm. As a result, a predictable path is
usually followed towards the pelvis and from the pelvis, along the right paracolic
gutter, towards the subdiaphragmatic space.32 Cancer cells also possess active motility
provided by lamellipodia and filipodia, whose mechanical force is generated by
polymerization of actin microfilaments.33

3. Mesothelial adhesion

Free peritoneal cancer cells adhere to either the mesothelial lining or to the underlying
extracellular matrix (ECM) through specific adhesion molecules. Mesothelial cells
express VCAM-1, ICAM-1, and PECAM-1, but not ICAM-2 or E-selectin.34, 35 Ziprin
et al. showed that in vitro, colorectal tumour - mesothelial adhesion was mediated by
the interaction of mesothelial ICAM-1 and CD43 (sialophorin) rather than β2 integrin,
the most ubiquitous ligand of ICAM-1.36 Adhesion between tumor cells and ECM
components seems to be mediated primarily by the beta 1 integrin subunit.37
Interestingly, the major omentum is a preferential site of peritoneal tumor growth. The
mechanisms underlying this specificity are not fully elucidated. It has been suggested
that cancer growth is stimulated by the pro-angiogenic environment of the omental
‘milky spots’, which consist of immune aggregates and a dense capillary network.38
Sorensen et al. showed that tumor cell binding may be mediated by a network of
collagen I fibers overlaying the milky spots, and that omental microvessels express
the pro-angiogenic vascular endothelial growth factor receptor 3 (VEGFR3).39
The expression of mesothelial adhesion molecules (and the resulting cancer cell
adhesion) may be considerably enhanced by inflammatory stimuli induced by
infection or surgical trauma.40 Thus, mesothelial expression of ICAM-1 is stimulated
by proinflammatory cytokines such as TNF-α, IL-1β, IL-6, and the epidermal growth
factor.41 Also, malignant cells may become entrapped in exudated fibrin matrices, and
exudated plasma proteins such as fibronectin and vitronectin may act as bridging
molecules between endothelial cells, smooth muscle cells and cancer cells via the α5β1
and αvβ3 receptors.42 Alterations in mesothelial binding may also be caused by
mechanical factors. In vitro, elevation of the ambient pressure (for instance by
establishing a pneumoperitoneum) increases adhesion of colon cancer cells to matrix
proteins.43 Also, elevated intraperitoneal pressures cause contraction of mesothelial
cells resulting of increased exposure of ECM binding sites.44 Apart from the
mechanical effects on mesothelial structure, the acidification and dehydration
associated with CO2 gas inflation during laparoscopic surgery were shown to promote
tumour growth and invasiveness in a number of preclinical studies.45, 46 Despite the
concerns raised by these preclinical models, the incidence of port site metastases has
been noted to decrease with appropriate protective measures such as trocar fixation,
adequate wound protection, and avoidance of desufflation through a skin incision. In
colorectal cancer, the results of recently completed large randomized trials comparing
open with laparoscopic colectomy demonstrated that the rate of wound recurrence is
low (<1%) and does not differ between the open and laparoscopic technique.47, 48

4. Invasion of the submesothelial tissue

Loose tumour cells gain access to submesothelial tissue at areas of peritoneal

discontinuity or mesothelial cell contraction. Alternatively, tumour cells can induce
apoptosis of mesothelial cells. Heath et al. demonstrated FAS dependent apoptosis of
cultured human mesothelial cells induced by SW480 colorectal tumour cells.49 Once
the mesothelial barrier is breached, tumor cells degrade the underlying matrix by
secretion of several proteases such as the matrix metalloproteinases (MMP).50, 51

5. Systemic metastasis

Peritoneal cancer cells can gain access to the lymphatic circulation through
specialized lymphatic stomata, which are localized mainly on the diaphragmatic
surface, falciform ligament of the liver, and pelvic side wall.52 These stomata are 8-10
µm2 round to oval gaps between cuboidal mesothelial cells and communicate directly
with the lumen of a lymphatic vessel or lacuna.53 In a rabbit model, passage from
cancer cells from the peritoneal cavity via the stomata into the lymphatic cisterna was
demonstrated.54 Importantly, both the density and diameter of the stomata and thus the
peritoneal absorptive capacity may increase by raised intraperitoneal pressure or by
molecular mediators such as VEGF and nitric oxide (NO).55

Prevention of Peritoneal Colorectal Metastasis

1. Reduction of Surgical Trauma

Surgical trauma may be prevented by physical measures such as the use of atraumatic
gauze or non powdered gloves.56, 57 Compared to open surgery, the use of laparoscopic
techniques minimizes peritoneal trauma and reduced tumour growth compared to
open surgery in several animal models, a finding usually attributed to a difference in
postoperative immune competence.58-60 Sylla et al. studied splenic T cell gene
expression following laparotomy versus CO2 pneumoperitoneum in a mouse model
and found that 177 genes were increased and 15 decreased at least 2-fold after
laparotomy relative to pneumoperitoneum.61

2. Peritoneal irrigation
Exfoliated cancer cells may be eradicated by irrigation of the peritoneal cavity, either
mechanically or by using a tumoricidal solution. There is some evidence from
preclinical studies that instillation of povidone-iodine (PVD) is beneficial.62 Basha et
al. showed that instillation of Povidone-iodine was effective in preventing tumour
take in a rat model when a limited tumour inoculum was used.63 In an animal model of
laparoscopy assisted tumour splenectomy, abdominal irrigation with dilute PVD
significantly reduced the number of animals with peritoneal implant metastases.64
Many of the commonly used antiseptics, however, are known to be inactivated by the
presence of blood.65 Huguet et al. used distilled water to achieve osmotic lysis of
cancer cells.66 Complete lysis in vivo took significantly longer (more than 30 minutes)
compared to in vitro instillation. Clinical studies using these approaches have not
been reported, and potential toxicity of intraperitoneal PVD should be kept in mind.67

3. Intraperitoneal Chemotherapy

In animal models, intraperitoneal instillation of chemotherapy was shown to be ef-

fective in preventing cancer cell implantation.68, 69 Nordlinger et al. reported a
randomized trial in which 753 patients with stage II or III colorectal cancer were
assigned to adjuvant systemic chemotherapy alone or immediate postoperative
regional chemotherapy (5-fluorouracil intraperitoneal or intraportal according to
treatment center) followed by systemic chemotherapy.70 No differences were observed
in overall survival or disease free survival, although the incidence of peritoneal
recurrence is not reported. Since intraperitoneal chemotherapy was administered
postoperatively, one may assume that postoperative adhesions prevented uniform
access of the instilled drug to the peritoneal cavity. This obstacle may be overcome by
intraoperative administration of chemotherapy, usually as a component of
hyperthermic intraoperative chemoperfusion (HIPEC), a strategy shown to benefit
colorectal cancer patients with resectable peritoneal carcinomatosis.4, 71, 72 A similar
approach consisting of ‘prophylactic’ HIPEC could reduce the risk of peritoneal
recurrence in high risk CRC patients. This hypothesis was provided initial
confirmation Elias et al., who performed second look surgery in 29 asymptomatic
CRC patients at high risk of peritoneal recurrence (resected minimal peritoneal
implants, synchronous ovarian metastases, or perforated tumours).73 Peritoneal
carcinomatosis undetected on imaging studies was present in 16 (55%) patients and
treated with surgery followed by intraperitoneal hyperthermic chemoperfusion,
resulting in a disease free status in half of the patients after a median follow up of 27
months. No signs of carcinomatosis were found in the remaining 13 patients, six of
whom underwent ‘prophylactic’ HIPEC. Interestingly, none of these six patients
recurred intraperitoneally while three out of seven patients who did not undergo the
HIPEC procedure did recur in the peritoneal cavity. These preliminary findings
formed the rationale of an ongoing randomised trial by the US National Cancer
Institute (ClinicalTrials.gov ID: NCT01095523).

4. Inhibition of Postoperative Growth of Peritoneal Residual Cancer Cells

It has been realised that the mechanisms involved in postoperative wound healing
may stimulate the growth of residual cancer cells.74 One of the essential features of
both wound healing and tumor growth is angiogenesis. Therefore, postoperative
inhibition of angiogenesis may prevent the outgrowth of peritoneal residual cancer.
Understandably, however, inhibition of VEGF in the postoperative setting carries the
risk of anastomotic and wound healing complications.75 Thus, in the National Surgical
Adjuvant Breast and Bowel Project (NSABP) C-08 trial which compared adjuvant
chemotherapy (FOLFOX6) with or without bevacizumab in stage II or III CRC, the
proportion of wound complications (incisional hernia, wound dehiscence, and port-
site dehiscence) was significantly higher in patients who received bevacizumab (1.7%
versus 0.3%, P < 0.01).76
Alternatively, one may avoid or suppress the inflammatory response after surgery. In
a mouse model, Roh et al. found that the selective cyclooxygenase-2 (Cox-2) inhibitor
celecoxib had a significant inhibitory effect on tumour growth in the surgical wound
when administered daily from 1 day before surgical wounding and tumour
implantation.77, 78 Also, restauration of surgery induced immunosuppression may
prevent postoperative locoregional cancer growth.40, 79 Small clinical trials in CRC
patients have shown that perioperative systemic administration using IL-2, GM-CSF,
or interferon restores postoperative immune function.80-82 However, their effect on
postoperative recurrence or survival is not known. In preclinical models,
intraperitoneal immunotherapy using cytokines, monoclonal antibodies, or
radionucleotide antibody conjugates has been successfully used to treat or prevent
peritoneal carcinomatosis.83

5. Inhibition of Adhesion of Free Intraperitoneal Cancer Cells

Specific therapy targeting the various mechanisms of tumour-mesothelial interaction

has been addressed in preclinical studies. One approach has been directed towards the
binding sites of the extracellular matrix (ECM). Alkhamesi et al. showed that
intraperitoneal application of heparin caused a significant decrease in tumour cell
adhesion accompanied by a decrease in ICAM-1 expression.84 Expression of ICAM-1
is also blocked in vitro by the grape polyphenol, resveratrol.85 Similarly, low
molecular weight heparin significantly reduced tumour growth following laparoscopy
in a rat colorectal cancer model.86 Heparins also inhibit tumour induced production of
thrombin, fibrin, and tissue factor, all of which have been implicated in primary and
metastatic tumour growth, and block P-and L-selectin mediated cell adhesion.87, 88
Alternatively, covering the ECM binding sites with a phospholipid emulsion reduced
tumour-mesothelial cell adhesion in animal models.89 Targeting of specific adhesion
molecules such as integrins90-92, L1 cell adhesion molecule93 and JAM-C94 with
monoclonal antibodies has shown to be effective in preventing tumour adhesion
and/or growth in preclinical models and may represent a future clinical therapeutic
tool.

Conclusion

Patients with locally advanced intraperitoneally located CRC are at risk of developing
peritoneal metastatic disease. It is increasingly acknowledged that peritoneal spread
represents a distinct disease manifestation, characterised by well defined stepwise
progression. The risk of peritoneal recurrence may be reduced by avoiding or
minimising surgical trauma, reducing the postoperative inflammatory response, and
by avoiding postoperative immunosuppression. Outgrowth of peritoneal cancer cells
may be abolished by intraperitoneal chemotherapy or tumoricidal solutions; clinical
trials are underway to establish the merit of these approaches.
Table 1. Incidence and prognostic significance of minimal residual disease in colorectal cancer

Author year N method markers or antibodies Detection rate Comments or Conclusion

Juhl95 1995 67 ICC C1P83 (CEA), Ra96, CA19-9 27% Positive ICC correlates with OS in univariate analysis
17-1A, C54-0, Kl-1
Hase96 1998 140 CYT 16% CYT positivity at the end of surgery predicts local recurrence

Schott97 1998 109 ICC C1P83 (CEA), CA19-9, 17-1A, 31% Positive ICC correlates with OS in univariate analysis
Ra96, C54-0, Kl-1
Wind98 1999 88 CYT 28% Presence of CYT+ cells provides no prognostic information

Vogel99 2000 90 CYT and ICC** HEA-125 47% Positive ICC does not predict local recurrence or outcome
100
Vogel 2001 135 ICC C1P83 (CEA), Ra96, CA19-9 23% Detection of ip tumor cells correlates with prognosis in univariate analysis
Worst prognosis in the presence of CEA positive intraperitoneal cells

Broll101 2001 75* ICC and RT-PCR CEA 63% CEA mRNA detection by RT-PCR not recommended due to high FP rate; presence
of ICC + cells represents independent prognostic factor in multivariate analysis

Lucha102 2002 56 CYT 2% Only 1 patient with + cytology

Aoki103 2002 20 RT-PCR CEA, CK20 24% Detection rate increased in parallel with invasion depth
104
Guller 2002 39 qRT-PCR CEA, CK20 28% Presence of PCR+ cells associated with worse DFS and OS in multivariate
analysis

Yamamoto105 2003 189 CYT 6% Presence of CYT+ cells predicted peritoneal recurrence and represents an independent
prognostic factor in multivariate analysis

Kanellos106 2003 110 CYT 20% Presence of CYT+ cells predicts locoregional recurrence but not survival

Bosch107 2003 53 CYT and ICC Ks20.8 (CK20), Ber-Ep4 17% Presence of CYT and/or ICC+ cells in blood and peritoneal lavage fluid
associated with DFS and OS in multivariate analysis

Lloyd108 2006 125 immunobead CK20, CEA, EphB4,LAMγ2, 29% Presence of PCR+ cells in post resection lavage fluid predicts DFS in multivariate ana-
RT-PCR matrilysin lysis (stage I and II cancers)

Kanellos109 2006 95 CYT and [CEA] 26% Presence of CYT+ cells and high peritoneal CEA level predicts recurrence but not OS

Gozalan110 2007 88 CYT 15% Presence of CYT + cells did not predict locoregional or systemic recurrence and does
not provide prognostic information

Hara111 2007 128 qRT-PCR CEA, CK20 23% Presence of PCR + cells is not an independent prognostic factor in multivariate
analysis and does not predict peritoneal recurrence

Kristensen112 2008 237 PCR for k-RAS mutation 8% Mutated k-RAS in peritoneal lavage samples following rectal cancer resection
Is associated with worse OS

Noura113 2009 697 CYT 2.2% Positive CYT is an independent prognosticator of cancer specific survival and
Peritoneal recurrence
Fujii114 2009 298 CYT 6% CYT status before resection does not affect survival or peritoneal recurrence

CYT, cytology; ICC, immunocytochemistry; RT-PCR, reverse transcriptase polymerase chain reaction; OS, overall survival; DFS, disease free survival; *includes 17 stomach cancer and 9 pancreas cancer cases;
** in a subset of 36 patients
Table 2. Incidence and prognostic significance of peritoneal involvement (pT4) of the resected colorectal cancer specimen

Author year N Stage II Stage III Detection rate Comments or Conclusion

Shepherd115 1997 412 42% 52% 27%* Peritoneal involvement significantly associated with OS in multivariate analysis; present in 45 of 46
patients who developed peritoneal recurrence

Solomon116 1997 103 47% 53% 14.6% Only the type of surgery predicted peritoneal involvement in univariate analysis; higher incidence in
rectal procedures

Lennon117 2003 118 100% - 13.6% Peritoneal involvement significantly associated with 5 year survival in multivariate analysis

Baskaranathan118 2004 281 63% 37% 9.3% Peritoneal involvement significantly associated with cancer specific survival in multivariate analysis

Keshava119 2007 665 49.9% 50.1% 5.3% Serosal involvement significantly associated with local recurrence and OS in multivariate analysis

Stewart120 2007 82 100% - 22% Serosal invasion associated with 5 year survival in univariate analysis
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