cancers

Review
Peritoneal Metastasis: Current Status and Treatment Options
Lilian Roth 1 , Linda Russo 1 , Sima Ulugoel 1 , Rafael Freire dos Santos 1 , Eva Breuer 1 , Anurag Gupta 1
and Kuno Lehmann 1,2, *
1 Surgical Oncology Research Laboratory, Department of Surgery & Transplantation,
University Hospital of Zurich, Raemistrasse 100, 8091 Zurich, Switzerland; [email protected] (L.R.);
[email protected] (L.R.); [email protected] (S.U.); [email protected] (R.F.d.S.);
[email protected] (E.B.); [email protected] (A.G.)
2 University of Zurich, 8006 Zurich, Switzerland
* Correspondence: [email protected]; Tel.: +41-44-255-11-11

Simple Summary: Surgical and locoregional treatments of peritoneal metastasis, e.g., from colorectal
cancer, has gained increasing acceptance after the publication of excellent patient outcomes from
many groups around the world. Apart from systemic chemotherapy and surgical removal of the
tumor, locoregional therapies such as HIPEC or PIPAC may improve tumor control. Understanding
the molecular characteristics of peritoneal metastasis is crucial to evolve future therapeutic strategies
for peritoneal metastasis. This includes the genetic background of PM, which is often different
from other sites of metastasis, and promotes peritoneal dissemination and the growth of tumor cells.
Growing knowledge and insight into the physiology of the peritoneal tumor microenvironment and
the specific role of the immune system in this compartment may provide a critical step to move
locoregional therapy to the next level. This review summarizes the current knowledge and highlights
the molecular characteristics of peritoneal metastasis.

Abstract: Peritoneal metastasis (PM) originating from gastrointestinal cancer was considered a





 terminal disease until recently. The advent of better systemic treatment, a better understanding of
Citation: Roth, L.; Russo, L.; Ulugoel, prognostic factors, and finally, the advent of novel loco-regional therapies, has opened the door
S.; Freire dos Santos, R.; Breuer, E.; for the multimodal treatment of PM. These strategies, including radical surgery and hyperthermic
Gupta, A.; Lehmann, K. Peritoneal intraperitoneal chemotherapy (HIPEC) showed surprisingly good results, leading to the prolonged
Metastasis: Current Status and survival of patients with peritoneal metastasis. This has triggered a significant body of research,
Treatment Options. Cancers 2022, 14, leading to the molecular characterization of PM, which may further help in the development of novel
60. https://doi.org/10.3390/ treatments. This review summarizes current evidence on peritoneal metastasis and explores potential
cancers14010060
novel mechanisms and therapeutic approaches to treat patients with peritoneal metastasis.
Academic Editor: David Wong
Keywords: peritoneal metastasis; colorectal cancer (CRC); cytoreductive surgery; hyperthermic
Received: 25 October 2021
intraperitoneal chemotherapy; tumor biology
Accepted: 20 December 2021
Published: 23 December 2021

Publisher’s Note: MDPI stays neutral

with regard to jurisdictional claims in 1. Introduction
published maps and institutional affil-
Peritoneal metastasis (PM) often arises from colorectal cancer (CRC). In a recent report,
iations.
epidemiological patterns of colorectal metastasis were well characterized, revealing that
almost one-third of CRC patients have metastatic lesions in the liver, where it often occurs
as a single site metastasis. In contrast, about 20% of CRC patients have metastasis in the
Copyright: © 2021 by the authors.
peritoneum, which often occurs together with other sites, and is associated with mucinous
Licensee MDPI, Basel, Switzerland. histology [1]. About half of patients with PM present with synchronous disease, the others
This article is an open access article with metachronous metastasis [2]. The risk to develop metachronous PM was higher in
distributed under the terms and right-sided colon cancer, advanced tumor stage T4, advanced nodal stage N2, as well as in
conditions of the Creative Commons emergency surgery or non-radical resection of the primary tumor [2].
Attribution (CC BY) license (https:// A landmark French study, the so-called EVOCAPE-1 study, prospectively explored the
creativecommons.org/licenses/by/ outcome of patients with gastrointestinal PM. This study showed that the median overall
4.0/). survival of patients with PM is dismal, with 3.1 months [3]. Recent studies have presented

Cancers 2022, 14, 60. https://doi.org/10.3390/cancers14010060 https://www.mdpi.com/journal/cancers

Cancers 2022, 14, 60 2 of 14

a benefit of up to 51 months median overall survival of patients with PM from CRC after
CRS and HIPEC [4]. This dramatic difference in overall survival is the result of treatment
evolution and a better patient selection.
An important study from the United States compared outcomes of patients with
different sites of metastasis under palliative treatment [5]. This study, including a large
number of patients, showed an inferior outcome of patients with PM compared with
hematogenous metastatic sites. However, this study lacked adequate intraoperative staging
and visual assessment of the PCI. This drawback has been addressed in a recent study
which compared the outcomes of patients after radical systemic and local treatment for
PM, according to sites of recurrent disease [4]. This multicenter study was able to demon-
strate an impaired outcome in patients with peritoneal recurrence when compared with
hematogenous recurrence. In addition, the authors also observed a different molecular
background for peritoneal lesions, which might be a driver for both the site of recurrence
and worse outcomes.

2. Genetic Alterations Associated with PM

Over the last decade, genetic analysis of human cancer has evolved enormously, pro-
moting better tumor classifications, improving treatment decisions, and finally enabling
personalized treatment strategies. Specific genetic alterations and mutations in PM largely
remain unknown. However, it can be assumed that mutations associated with primary
tumors may offer a molecular understanding of PM. PM often arises from colorectal cancer,
for which genetic understanding has been well characterized [6]. It is known that in CRC,
at least seven mutations occur during adenoma-to-carcinoma transformation [7]. In CRC,
the loss of APC, mutations in TP53, KRAS, TGF-β and PIK3CA genes, and loss of the
chromosome arm 18q are well characterized [8]. Deep molecular assessment has revealed
that malignant transformations involve additional steps, e.g., alterations in the promotor
region of CpG island tandem repeats of mismatch repair genes such as MLH1, MSH2,
MSH6, PMS2, STK11 and SMAD2/4 were identified to cause epigenetic silencing of these
genes. Such alterations cause chromosomal instability (CIN), which is common in 65–70%
of sporadic CRC [8,9]. CIN can also be promoted by the mutations of genes involved in
chromosome segregation (BUB1, AURKA, PLK1, etc.), telomere regulation (TERC) and
DNA damage response (ATM, ATR and BRCA1/2). CIN leads to aneuploidy, subchro-
mosomal gene amplification and a high frequency of loss of heterozygosity, promoting
metastatic spread [8]. In contrast, microsatellite instability (MSI), resulting from a defect in
mismatch repair genes, can cause a further increase in metastatic potential [9].
Following molecular assessments such as genetic mutations and MSI status, it is
possible to categorize CRC into biologically different tumor types that may also predict
clinical prognosis [10]. However, this classification, into the four consensual molecular
subtypes, has not yet fully been developed into clinical practice and decision making for
targeted therapies or immune therapies, with the exception of the MSI status, which is an
accepted selection criterion for checkpoint inhibition. Together with an increasing body of
molecular insights into the pathogenesis of CRC, our perception of metastatic diseases is
constantly evolving. Currently, a handful of specific genetic alterations are recognized as
an underlying mechanism, or at least a hallmark, of a specific metastatic site. For example,
differences in APC, BRAF, KRAS and NRAS are associated with the location of the primary
tumor in right or left hemicolon [11]. Among them, mutations in KRAS and BRAF were
associated with worse overall survival and the site of recurrence in patients with PM [4,12].

3. Molecular Steps from Primary to Peritoneal Metastasis

The metastatic cascades of CRC that follow PM development show similarities with
other types of metastases. It has been proposed that it may start with the exfoliation
of single cells or tumor clumps and, in some cases, via tumor spheroids with inverted
polarity (TSIPs) [13]. Exfoliation is initiated upon the downregulation of different adhesion
molecules at the cell surface, mostly involving E-cadherin [14]. Another factor that may be
Cancers 2022, 14, 60 3 of 14

involved in exfoliation is CNN3, a potential metastasis marker [15]. CNN3 is expressed

in different cell types where it binds to actin, calmodulin, troponin C and tropomyosin,
and is involved in the regulation and modulation of smooth muscle contraction. Its
role in other cells is not yet identified; however, it may play a role in cell motility and
invasiveness, because knockdown of this gene results in the decreased invasiveness of
metastatic cancer cell lines. In addition, CNN3 may contribute to the initial dissemination of
tumor cells by downregulating the adhesion molecule E-cadherin in the primary tumor [15].
Exfoliation is then followed by epithelial to mesenchyme transition (EMT), where cancer
cells gain mesenchymal properties, e.g., the upregulation of N-cadherin, loss of cell polarity
and vimentin expression. This cadherin switch is also essential during the formation of
peritoneal metastasis from serous ovarian cancer [16]. Cancer cells acquire motility, become
invasive and increase the resistance to apoptosis [17]. Moreover, it was shown that in solid
tumors such as CRC, high intestinal fluid pressure may contribute to spontaneous tumor
cell shedding, supporting cancer cell distribution in the surrounding lymph nodes [18].
In a next step, via transmesothelial or translymphatic dissemination, free CRC cells
can attach to the distant peritoneum. During transmesothelial dissemination, cancer cells
adhere directly to the mesothelium, which consists of a monolayer of mesothelial cells sup-
ported by a thin basement membrane. Below the basement membrane is the submesothe-
lium, which harbors cellular (fibroblast, macrophages, endothelial cells, etc.) and acellular
(collagen, glycoproteins, proteoglycans, etc.) components [14,19]. Adhesion molecules of
the immunoglobulin superfamily, such as ICAM-1, PECAM-1 and VCAM-1, are known to
favor mesothelial–cancer interactions. Furthermore, pro-inflammatory cytokines such as
TNF-α, IL-1β, IL-6 and INF-γ can promote the expression of the immunoglobulin super-
family and induce the contraction of mesothelial cells, exposing the basement membrane
to facilitate invasion. In addition to adhesion molecules, the glycosaminglycan hyaluronan
can enhance mesothelial–cancer interactions. The mesothelial cells secrete hyaluronan,
which binds to the CD44 receptor on cancer cells [14,15]. Moreover, it has been shown that
the CD44v6 isoform in patients with stage II/III CRC show poor prognosis in terms of
overall survival and disease-free survival [20]. Mechanistically, isoform CD44v6 in CRC
inversely correlates with E-cadherin expression and exhibits a positive correlation with
vimentin. Detached cancer cells may also metastasize using translymphatic route. To
access the submesothelium, cells pass through lymphatic vessels, which normally serve
as drainage channels for the serous cavities and as migration passages for macrophages.
Similar to ascites and infectious components, cancer cells use lymphatic vessels to accu-
mulate in milky spots. Milky spots are macrophage-rich aggregates. Milky spots in the
murine omentum seem to possess a pronounced vascular microenvironment that may
favor the early survival of cancer cells [21] via VEGF and CD105 expression [21]. Once
cancer cells attach to the mesothelium, they invade into the subperitoneal space either at
areas of peritoneal discontinuity or by actively altering the monolayer. Discontinuity occurs
due to prior peritoneal injury, for example, via surgery or pro-inflammatory cytokines,
which induce the rounding of mesothelial cells resulting in the exposure of the basement
membrane [14].
An active alteration of the monolayer involves tumor-cell-induced mesothelial apop-
tosis via the death ligand/receptor system Fas Ligand/Fas [22]. Furthermore, Yao et al.
suggested the role of HGF/c-met pathway in patients with CRC metastases. In this study,
the authors found an increased expression of c-Met in metastases compared with the pri-
mary CRC tumor and a positive correlation of c-Met expression with tumor stages [23].
However, those findings were observed in CRC liver metastases. Thus, the role of c-Met in
peritoneal metastases from CRC remains to be explored.
Once in the sub-peritoneal space, cancer cells and the surrounding stromata cells
secrete matrix metalloproteinase (MMP), affecting the extra cellular matrix (ECM), and
allowing invasion and migration. High expression of MMP-1, -2, -7, -9 and -13 was shown
to correlate with worse outcomes [24]. Tissue inhibitors of metalloproteinase (TIMPs) are
known to inhibit the proteolytic activity of MMPs; however, increased TIMP-1 and TIMP-2
Cancers 2022, 14, 60 4 of 14

concentrations in serum seems to be associated with worse prognosis [25,26]. After suc-
cessful dissemination in metastatic sites, cancer cells stimulate sustained proliferation via
the secretion of growth factors in the surrounding tumor-associated stroma. For example,
insulin-like growth factor 1 (IGF-1) was found to be overexpressed in PM from CRC [26].
Additionally, increased plasma levels of IGF-binding protein 3 (IGFBP3), an endogenous
antagonist of IGF-1, was found to correlate with lower progression and an improved
treatment response [27]. Furthermore, cancer cells release HIF-1α, which regulates the
production of VEGF, to access nutrients and oxygen. A study performed by Varghese
et al. on 20 metastatic tumors from patient with colorectal adenocarcinoma indicated
that peritoneal metastases overexpressed HIF-1α, TIMP-2 and IGF-1 compared with other
metastatic sites [26].
Taken together, the induction of peritoneal metastasis involves a complex cascade,
starting with tumor cells exfoliation, epithelial-to-mesenchyme transition, attachment, and
invasion towards deeper layers by a transmesothelial or translymphatic route; thus, it can
be summarized as peritoneal metastatic cascade [14]. The above-mentioned mechanisms
are driven mainly by the biology of the tumor cells; however, there is another major player
controlling malignant disease: the immune system.

4. Immune Reactions towards Peritoneal Metastasis

More than 100 years ago, in 1909, Paul Ehrlich suggested that the immune system may
control tumor development [28]. Almost 50 years after Ehrlich, Brunet and Thomas made an
unproven claim that lymphocytes can eliminate transformed cancerous cells. The most ele-
gant experiments regarding the immunosurveillance of cancer came from Robert Schreiber,
who introduced the 3E concepts of immunoediting during cancer development [28,29].
The 3Es stand for elimination, equilibrium and escape. In the elimination phase, which
is difficult to study experimentally, it is assumed that aberrant cells are actively removed
by the immune system. Escape from elimination allows transformed cells to remain in an
equilibrium phase, where transformed cells remain on watch and are actively controlled by
the immune system, keeping them in a dormant state for many years. However, during
this dynamic equilibrium phase, it may happen that cancer cells develop strategies making
immune recognition futile. As soon as immune inhibitory changes occur, cancer cells enter
the escape phase, leading to the development of clinically apparent cancers [28,29].
The immunoediting process illustrates that if the immune system can be reprogramed
to recognize cancer, it will be possible to regain control overgrowth of cancer or metastatic
lesions. Many research projects over the past two decades have generated a solid body
of evidence indicating that the presence of lymphocytes, especially functional CD8+ T
cells, is crucial to control tumor growth. This finding has promoted the evolution of
immunotherapies, either involving the transfusion of antigen-specific CD8+ T cells, so
called CAR T cells, or antibodies that allow the sustained activation of functional CD8+ T
cells. The antibodies target so-called checkpoint blockade molecules such as PD-1, LAG-3,
PD-L1 and CTLA-4 [30], and are only effective if sufficient numbers of CD8+ T cells are
present within immunogenic tumors. The progress made in the treatment of metastatic
melanoma offering prolonged overall survival for a majority of patients illustrates the
success of immunotherapy. Unfortunately, with the exception of microsatellite-instable
(MSI) colon cancer, immunotherapy thus far has demonstrated limited effects against
colorectal cancer (CRC).
Tumor microenvironment composition is a prognostic factor for overall and cancer-
specific survival, regardless of the lymph node, MSI and CpG island methylation status [31].
One important molecular phenotype of CRC is the sporadic or hereditary (Lynch Syndrome)
defect in mismatch repair proteins, which leads to MSI. Approximately 15% of all CRCs
harbor a microsatellite instability and are associated with a better prognosis [32,33]. The
defect in the mismatch repair machinery is either sporadic, caused by the gene silencing
of MLH 1, or by a germline mutation of MLH 1 and 2 in Lynch Syndrome. Colon cancer
with an MSI phenotype shows a presence of more neoantigens and a higher degree of
Cancers 2022, 14, 60 5 of 14

tumor-infiltrating lymphocytes [34,35] leading to a better immune-recognition, and finally,

improved CRC-specific survival [35].
In the context of peritoneal metastasis, the role of the immune system in controlling PM
development remains unexplored. From liver metastasis, we have learned that cytotoxic
(CD8+) T cells seem to play a role. Liver metastasis from colon cancer is associated
with a higher CD8/CD3 ratio than liver metastasis from rectal cancer, and has a better
progression-free and overall survival [36]. Compared with primary colon cancer, the PM
microenvironment shows more NK cell infiltration and more senescent tumor cells [37].
Upon the analysis of n = 43 PM samples from gastric cancer, a higher accumulation of
resting CD4+ T cells in an aggressive gastric tumor phenotype was found. In contrast, the
numbers of cytotoxic T cells, NK cells and myeloid dendritic cells were lower in advanced
(G2 vs. G3) and histologically aggressive stages (signet ring vs. non-signet ring). This can
be interpreted as an immunosuppressive tumor microenvironment, induced by cancer cells,
to facilitate tumor progression. Furthermore, based on the T cell infiltration profile, patients
could be divided into T-cell-exclusive and T-cell-exhausted. The T-cell-exclusive group
exhibited a low expression of CD8+-T-cell-related cytokines and the immune checkpoint
TIM-3, whereas the T-cell-exhausted immune cell infiltrate was characterized by a high
expression of cytolytic markers and TIM-3 [38].
The role for CD8+-mediated immunity in peritoneal metastasis from CRC remains
elusive. However, some evidence is available from patients with epithelial ovarian cancer,
where a higher intra-tumoral CD8+ T cell/Tregs ratio was also associated with a prolonged
survival [39]. This observation corelates with the clinical observation of tumor dissemina-
tion in high-grade serous ovarian cancer, where one group proposed a new classification
of peritoneal spread into miliary and non-miliary cancer [40]. A non-miliary pattern of
peritoneal metastasis was associated with a better survival regardless of clinicopathological
factors, due to more CD8+ T cells with a higher expression of PD-1 and PD-L1 on tumor
cells, indicating an activated specific immune response, whereas the miliary form was asso-
ciated with signs of a systemic inflammation [41]. In addition, PD-L1 expression on primary
ovarian cancer is 66% concordant with its peritoneal metastasis, regardless of any signifi-
cant correlation with the overall survival, progression-free survival and disease-specific
survival [42].

5. CRS and HIPEC, a Locoregional Treatment Approach for Peritoneal Metastasis

A few decades ago, patients with PM from colorectal cancer (CRC) had a poor prog-
nosis and seemed incurable [43]. Over recent years, the management and treatment of
PM has undergone major developments [44]. The introduction of cytoreductive surgery
(CRS), together with hyperthermic intraperitoneal chemotherapy (HIPEC), gave hope to
patients with PM [45,46]. During CRS/HIPEC, to eradicate residual microscopic cancer
cells, a heated solution with chemotherapeutic agents is applied perioperative directly
into the peritoneum after macroscopically visible tumor nodules have been surgically
removed. Historically, extensive debulking surgery started in around 1930 by J.V. Meigs
for ovarian cancers, and the importance of cytoreductive surgery and, subsequently, of
adjuvant chemotherapy became more evident over the next decades, not only for ovarian
cancer, but also for pseudomyxoma peritonei [47–50]. With the increasing use of adjuvant
chemotherapy, the idea of intraperitoneal application emerged to increase the therapeu-
tic index [51]. In the following years, several trials with CRS/HIPEC and optimization
attempts with different chemotherapeutic agents, depending on histological origin, were
conducted [44]. To date, two main surgical intraperitoneal delivery techniques of hyper-
thermic intraperitoneal chemotherapy have been described: the open coliseum technique
and closed administration [52]. In the 1990s, Sugarbaker and his team proposed the peri-
toneal cancer index (PCI) as a standardized scoring system to quantify peritoneal tumor
burden during an operation, and the completeness of cytoreduction score (CC score) to
determine how radical the surgery was [53]. The introduction of these scores is relevant
for the selection of patients for CRS/HIPEC or to compare results among centers [54].
Cancers 2022, 14, 60 6 of 14

The contemporary staging of PM is performed with the peritoneal cancer index (PCI), a
staging system ranging from 0 to 39 points, which adequately describes the distribution
and the size of PM in a patient [55]. The comparison of PM with other metastatic sites is
often problematic. Imaging modalities (e.g., computed tomography or magnetic resonance
imaging) are more sensitive for metastasis in the lung or liver. Nevertheless, a review
article on imaging diagnoses of PM from gastrointestinal and ovarian cancer showed an
adequate pooled sensitivity and specificity of 80% and 90%, respectively, for PET-CT, and
92% and 85% for MRI. The authors claim that MRI could become the imaging modality
of choice in staging PM, because MRI is already widely available [56]. In a clinical trial
(NCT03314649), the role of mutated DNA of cancer cells in the abdominal cavity of gastric
cancer patients is assessed, with the goal of increasing sensitivity in the diagnosis of mi-
crometastasis. Another interesting approach is the detection of peritoneal implants from
CRC with near-infrared fluorescence imaging after the i.v. administration of indocyane
green (ICG) (NCT02032485). Even though many new strategies in the diagnostic procedure
are currently being investigated, current clinical practice still relies on the surgical staging
of PM by either laparoscopy or laparotomy [57].
Although the surgical concepts for cytoreduction are standardized, no standardization
has been established thus far for HIPEC protocols with regard to temperature, treatment
duration or the type of drug. Current HIPEC protocols for patients with colorectal PM
therefore lack consistency and differ among countries and hospitals. For example, one
proposed treatment protocol is the use of heated Oxaliplatin (Oxa), a third-generation
platinum forming intra- and interstrand crosslinks in the DNA, for 30 min at 43 ◦ C [58].
This protocol was also used in a prospective multicenter trial, PRODIGE-7. Patients
(n = 265) with stage IV colorectal cancer with isolated peritoneal metastases and a PCI < 25
were randomly assigned to CRS or CRS with an oxaliplatin-based HIPEC for 30 min. No
significant benefit regarding median overall survival could be shown by the addition
of HIPEC (median OS 41.7 versus 41.2 months). Despite this result, the subgroup of
patients with a PCI > 11 ≤ 15 demonstrated a significantly higher overall survival after
CRS/HIPEC compared with CRS only [59]. The efficacy of HIPEC in general, with other
drug combination, or at other concentrations cannot be answered by this study. Based
on the results from both treatment groups, the main message of PRODIGE7 is that CRS,
performed in expert centers, provides superior outcomes in patients with PM from CRC.
The optimal regimen for HIPEC and the added benefit remains elusive [59].
This result goes well with the observation from a previously completed, small (n = 105)
randomized trial comparing systemic chemotherapy with CRS/HIPEC [60]. Despite a weak
control arm, where patients received only 5-Fluorouracil (5-FU)-based systemic therapy,
the authors were able to show that CRS/HIPEC improved disease-specific survival from
12.6 months in the control arm to 22.2 months in the CRS/HIPEC [61]. In both trials,
patients who profited had a high peritoneal disease load.
In 2013, the American Society of Peritoneal Surface Malignancies recommended a
regimen with Mitomycin C (MMC) for 90 min at 42 ◦ C, which is now used widely [62,63].
MMC is an antitumor antibiotic, isolated from Streptomyces caespitosus, classified as an
alkylating agent causing cross-linking in the DNA. These crosslinks prevent the separation
of complementary DNA strands, inhibiting DNA replication [64]. The American random-
ized phase II study ICARuS with HIPEC using MMC is currently ongoing (NCT01815359),
and the adjuvant HIPECT 4 trial is enrolling patients to investigate the role of adjuvant
chemotherapy with MMC in order to prevent PM recurrence [65]. Apart from mono
regimens with oxaliplatin or mitomycin C, some groups use combination therapies with
mitomycinC/doxorubicin or irinotecan (IRI)/doxorubicin [63], although clinical trials with
combination therapies are still lacking.
As mentioned above, patient selection for CRS/HIPEC is key. Negative predictive
factors after CRS/HIPEC are the extent of the disease (PCI), nodal stage, tumor biology,
response systemic therapy or major complications after CRS/HIPEC. Some of these prog-
nostic factors can be summarized by clinical scores (e.g., PDSS or BIOSCOPE). For example,
Cancers 2022, 14, 60 7 of 14

BIOSCOPE includes the PCI, the nodal stage, tumor grading and the RAS/RAF mutational
status, and helps to discriminate prognostic groups [66]. In clinical practice, these scores
are usually not exclusive, but may help in the clinical decision process. After CRS/HIPEC,
a major complication (Clavien-Dindo classification IIIB or higher) rate of 8.3% to 24% has
been published in recent series [67,68].
HIPEC can also be performed as an adjuvant treatment to prevent peritoneal spread.
In their trial, Virzi et al. demonstrated the feasibility and safety of HIPEC in an adjuvant
setting, even though 16% of patients experienced major complications [69]. The COLOPEC
trial could not prove any benefit in peritoneal-free survival after adjuvant HIPEC compared
with the control arm [70].

6. The Rapid Development of Systemic Chemotherapy

Since the use of 5FU, the field of medical oncology has evolved dramatically and new
systemic regimens and targeted agents have significantly improved the survival of patients
with advanced stages of CRC [71]. Today, the choice of a systemic chemotherapy regimen
depends decisively on the molecular pathological profile of the tumor. Frequently used
systemic first-line regimens include combinations of 5FU or capecitabine with oxaliplatin
or irinotecan [18]. Triple therapy with 5FU, oxaliplatin and irinotecan (FOLFOXIR) is a very
effective regimen and has demonstrated superior response rates [72]. However, due to its
side effects, it is usually given to patients in a good health condition [73]. Targeted therapies,
e.g., cetuximab, an EGFR-antibody, or bevacizumab, a humanized IgG monoclonal antibody
targeting VEGF-A, are often added, depending on the molecular profile of the tumor.
Multiple trials, including the phase III CRYSTAL and PRIME study, showed that adding
an anti-EGFR to FOLFIRI and FOLFOX4, respectively, is beneficial for patients with RAS
wild-type tumors [20]. Overall, median overall survival has dramatically improved to
nearly 30 months in the context of aggressive chemotherapy, which often enables secondary
surgery of metastasis [72] (Table 1). The majority of patients included in these trials,
however, have hematogenous metastasis, which has a significantly better prognosis than
peritoneal metastasis [4,5]. Nevertheless, response to neoadjuvant systemic treatment is
also a prognostic factor in patients with PM [74]. Thus, progress in this field is likely to
enable more aggressive surgery in the future.

Table 1. Current data on the treatment of PM from CRC by either systemic therapy alone or in
combination with locoregional treatment. It is critical to highlight that the amount of disease in
the peritoneum or the chemotherapy regimen differed among the studies. (amount of disease: +++
extensive load of PM, ++ moderate load, + limited load, NA: not available).

PM—CRC Outcome after Different Treatment Approaches

mOS (Months)
Systemic Amount of
CRS/HIPEC PIPAC Used Drug
Chemotherapy Disease
Vervaal V. et al., 2003 [60] 22.2 12.6 - +++ 5FU
Elias D. et al., 2009 [58] 67.7 23.9 - ++ FOLFOX/FOLFIRI
FOLFOX/FOLFIRI
Franko J. et al., 2016 [5] 16.3 - - NA
+/−ab
Cremolini Ch. et al., 2020 [75] - 28.9 - NA FOLFOXIRI
Quenet F. et al., 2021 [59] 41 - - ++ FOLFOX/FOLFIRI
Breuer E. et al., 2021 [4] 51 - - ++ FOLFOX/FOLFIRI
FOLFOX/FOLFIRI
Demtröder C. et al., 2015 [76] - - 15.7 +++
+/−ab
mOS not reached during
Goére D. et al., 2020 [77] - + FOLFOX/XELOX
50.8 months of follow-up

7. Novel Concepts and New Treatment Strategies for the Treatment of PM

Apart from using HIPEC as a complementary treatment, directly after cytoreductive
surgery, some novel concepts have been introduced. Many of them highlight the palliative
aspect of PM. A good example is pressurized intraperitoneal aerosol chemotherapy (PIPAC),
Cancers 2022, 14, 60 8 of 14

where low-dose chemotherapy is applied intraperitoneally during laparoscopy as an aerosol

at a pressure of 12 mmHg, usually every four weeks. This method is currently used in
patients with non-resectable disease and is well tolerated [78]. The rationale for PIPAC is
a more homogeneous intraperitoneal distribution of chemotherapy in a closed space by
applying it as a pressurized aerosol, leading to increased chemotherapy concentrations
within the tissue compared with HIPEC [77,78]. PIPAC also offers a possibility to repeat the
treatment. A further development of PIPAC is electrostatic PIPAC (ePIPAC). Here, a phase
II study (NCT03246321) has completed patient recruitment using ePIPAC with oxaliplatin
as a palliative monotherapy for patients with isolated and unresectable PM-CRC.
There are multiple challenges in the diagnosis and treatment of peritoneal metastasis.
A major issue is the detection of minimal disease during surgery, where scars from previous
procedures are impossible to differentiate from metastatic lesions. Techniques such as
fluorescent-guided surgery could amplify detection sensitivity, making resections more
precise. Several therapeutic targets have being tested; among them, anti-CEA antibodies
have shown encouraging clinical results [79]. Another field of research is the delivery of
drugs into the peritoneal cavity. Here, apart from HIPEC or PIPAC, several technologies
have been investigated that may improve the exposure of PM lesions to cytostatic drugs. For
example, nanoparticles could provide several advantages, e.g., prolonged drug retention
time, controlled drug release, and serve as a versatile vector for different molecules [80].
The combined used of microspheres and hyaluronic acid hydrogel showed good results,
enhanced drug solubility, prolonged drug release and sustained biocompatibility [81].
Another innovative concept is NIPS, where a intraperitoneal catheter is placed into the
pelvic cavity to administer neoadjuvant intraperitoneal and systemic chemotherapy. In
patients with peritoneal metastasis from gastric cancer, NIPS resulted in a lower cancer-
cell-positive ascites rate and in a higher R0 resection rate [82].
Given the increasing knowledge on anti-tumor immunity in the peritoneum, immune
checkpoint inhibitors may play a role, not only in micro-satellite instability-high (MSI-
H), or mismatch repair-deficient (MMRd) metastatic colorectal or ovarian cancer [83–85].
Although the immune cell landscape in PM lesions is not yet established, locoregional
treatment may influence immunity in PM lesions. For example, anthracyclines—such as
doxycycline—induce immunogenic cell death (ICD) [86], which leads to the release of
DAMPs from dying cancer cells. DAMPs in combination with antigen release can result in
DC maturation and antigen presentation to CD8+ T cells [86,87]. After recognizing a specific
antigen, T cells clonally expand and can fight surviving cancer cells. Moreover, cisplatin
(also used for HIPEC) sensitized spontaneous lung cancer in a mouse model to induce a
checkpoint blockade via the induction of ICD. This immunogenic effect is mediated not
only by chemotherapy, but also radiotherapy; a single carefully selected dose is able to
mediate similar effects. Sharma et al. described an enhanced expression of cancer testis
antigens and MHC-I expression after the application of 20 Gy radiotherapy in vitro [88].
Taken together, locoregional therapy may induce ICD to activate the immune system. In the
context of HIPEC, the addition of hyperthermia might have an additional effect through
the induction of heat shock proteins. In mice, an Hsp-90-mediated anticancer immune
response was observed after the in vitro HIPEC treatment of murine cancer cells [89]. An
interesting example for a novel treatment approach for PM-CRC was provided by the phase
1 ImmunoPeCa trial. The immunotoxin MOC31PE was intraperitoneally administered one
day after CRS and HIPEC, with the intention of killing EpCAM-positive cancer cells and
preventing recurrence [90].
Despite the recent progress made, a deeper insight and molecular understanding
of effects during locoregional treatment on the human host physiology and the immune
system is required. Investigating tumor samples from PM patients and further assessments
of cytokine profiles before and after treatment could provide critical knowledge about
these processes. If surgery and locoregional treatment can induce anti-tumor immunity,
these patients might profit from an additional treatment to boost the immune reaction. The
rationale behind such a novel treatment approach is shown in Figure 1.
 system is required. Investigating tumor samples from PM patients and further assess-
ments of cytokine profiles before and after treatment could provide critical knowledge
about these processes. If surgery and locoregional treatment can induce anti-tumor im-
Cancers 2022, 14, 60 9 of 14
munity, these patients might profit from an additional treatment to boost the immune
reaction. The rationale behind such a novel treatment approach is shown in Figure 1.

Figure 1. Schematic view of mechanisms of locoregional treatment in the peritoneum: the current
Figure 1. Schematic view of mechanisms of locoregional treatment in the peritoneum: the current
interpretation of how HIPEC or PIPAC act on tumor cells is to induce cell death via direct cytotoxicity.
interpretation of how HIPEC or PIPAC act on tumor cells is to induce cell death via direct cytotoxi-
Growing evidence
city. Growing on immunogenic
evidence on immunogeniccell death suggests
cell death that the
suggests thatactivation of a patient’s
the activation immune
of a patient’s im-
system
mune might
systemmediate better long-term
might mediate disease disease
better long-term control control
throughthrough
the induction of T cells.
the induction of TThis process
cells. This
might bemight
process boosted in next-generation
be boosted treatment
in next-generation approaches
treatment and induce
approaches a profound
and induce and sustained
a profound and sus-
immune reactionreaction
tained immune against metastatic lesions.lesions.
against metastatic CreatedCreated with BioRender.com.
with BioRender.com.

8.8.Conclusions
Conclusionsand andOutlook
Outlook
Understanding
Understanding the the molecular
molecular characteristics
characteristics of of peritoneal
peritoneal metastasis
metastasis isis crucial
crucial to
to
evolve future therapeutic strategies for peritoneal metastasis. This includes
evolve future therapeutic strategies for peritoneal metastasis. This includes the genetic the genetic
background
backgroundof ofPM,
PM,which
whichisisoften
often different
different from
from other
other sites
sites of
of metastasis,
metastasis, andand promotes
promotes
peritoneal dissemination and the growth of tumor cells. Growing knowledge
peritoneal dissemination and the growth of tumor cells. Growing knowledge and insight and insight
into
intothe
thephysiology
physiologyof ofthe
theperitoneal
peritoneal tumor
tumor microenvironment
microenvironment and and the
the specific
specific role
roleofofthe
the
immune system in this compartment may provide a critical step
immune system in this compartment may provide a critical step to move locoregional to move locoregional
therapy
therapytotothe thenext
nextlevel.
level.
ItItisislikely
likely thatprogress
that progressmade
madeininsystemic
systemictreatment
treatmentregimens
regimenswill
willtranslate
translateinto
intobetter
bet-
response rates for peritoneal metastasis and enable radical treatment
ter response rates for peritoneal metastasis and enable radical treatment in more patients. in more patients.
Better
Betterknowledge
knowledge on on selection
selectioncriteria
criteria will
will helphelp to identify
to identify patients
patients who arewho are to
likely likely to
profit
profit from aggressive surgical treatment, whereas patients with an
from aggressive surgical treatment, whereas patients with an adverse risk profile may adverse risk profile
may undergo
undergo additional
additional locoregional
locoregional treatment,
treatment, e.g., PIPAC.
e.g., with with PIPAC. Finally,
Finally, optimal optimal drug
drug regi-
regimens for the locoregional treatment of PM remain unclear,
mens for the locoregional treatment of PM remain unclear, and the identification ofand the identification of
molecular mechanisms involved in long-term tumor control beyond cytotoxicity is critical.
Therefore, experimental, and translational research is critical in the next years.

Author Contributions: Conceptualization, L.R. (Lilian Roth), L.R. (Linda Russo), A.G., K.L; data
curation, L.R. (Lilian Roth), L.R. (Linda Russo)., S.U., R.F.d.S., E.B.; writing—original draft prepa-
ration, L.R. (Lilian Roth), L.R. (Linda Russo)., S.U., R.F.d.S., E.B.; writing—review and editing,
L.R. (Lilian Roth), L.R. (Linda Russo)., S.U., R.F.d.S., A.G., K.L., visualization, L.R.; funding ac-
quisition, A.G., K.L. All authors have read and agreed to the published version of the manuscript.
Cancers 2022, 14, 60 10 of 14

Funding: This work was supported by a research grant from the Swiss National Science Foundation
(310030_185029) to K.L.
Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations

CRS cytoreductive surgery

CRC colorectal cancer
DFS disease-free survival
HIPEC hyperthermic intraperitoneal chemotherapy
mOS median overall survival
MSI/MSS microsatellite instability/stability
PM peritoneal metastasis
PCI peritoneal cancer index
RCT randomized controlled trial

References
1. Riihimäki, M.; Hemminki, A.; Sundquist, J.; Hemminki, K. Patterns of metastasis in colon and rectal cancer. Sci. Rep. 2016, 6,
29765. [CrossRef] [PubMed]
2. Segelman, J.; Granath, F.; Holm, T.; Machado, M.; Mahteme, H.; Martling, A. Incidence, prevalence and risk factors for peritoneal
carcinomatosis from colorectal cancer. Br. J. Surg. 2012, 99, 699–705. [CrossRef] [PubMed]
3. Sadeghi, B.; Arvieux, C.; Glehen, O.; Beaujard, A.C.; Rivoire, M.; Baulieux, J.; Fontaumard, E.; Brachet, A.; Caillot, J.L.; Faure, J.L.;
et al. Peritoneal carcinomatosis from non-gynecologic malignancies: Results of the EVOCAPE 1 multicentric prospective study.
Cancer 2000, 88, 358–363. [CrossRef]
4. Breuer, E.; Hebeisen, M.; Schneider, M.A.; Roth, L.; Pauli, C.; Frischer-Ordu, K.; Eden, J.; Pache, B.; Steffen, T.; Hubner, M.; et al.
Site of Recurrence and Survival after Surgery for Colorectal Peritoneal Metastasis. J. Natl. Cancer. Inst. 2021. [CrossRef]
5. Franko, J.; Shi, Q.; Meyers, J.P.; Maughan, T.S.; Adams, R.A.; Seymour, M.T.; Saltz, L.; Punt, C.J.A.; Koopman, M.; Tournigand, C.;
et al. Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: An analysis of individual patient
data from prospective randomised trials from the Analysis and Research in Cancers of the Digestive System (ARCAD) database.
Lancet. Oncol. 2016, 17, 1709–1719. [CrossRef]
6. Yawar, B.; Babar, S.; Imaad Ur, R.; Sana, F.; Javed, F.; Chaudhary, M.Y. Multidetector CT Patterns of Peritoneal Involvement in
Patients with Abdominopelvic Malignancies. J. Coll. Physicians. Surg. Pak. 2015, 25, 399–402. [PubMed]
7. Fearon, E.R.; Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 1990, 61, 759–767. [CrossRef]
8. Pino, M.S.; Chung, D.C. The chromosomal instability pathway in colon cancer. Gastroenterology 2010, 138, 2059–2072. [CrossRef]
9. Karunasena, E.; Sham, J.; McMahon, K.W.; Ahuja, N. Genomics of Peritoneal Malignancies. Surg. Oncol. Clin. N. Am. 2018, 27,
463–475. [CrossRef]
10. Guinney, J.; Dienstmann, R.; Wang, X.; de Reyniès, A.; Schlicker, A.; Soneson, C.; Marisa, L.; Roepman, P.; Nyamundanda, G.;
Angelino, P.; et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 2015, 21, 1350–1356. [CrossRef]
11. Yaeger, R.; Chatila, W.K.; Lipsyc, M.D.; Hechtman, J.F.; Cercek, A.; Sanchez-Vega, F.; Jayakumaran, G.; Middha, S.; Zehir, A.;
Donoghue, M.T.A.; et al. Clinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer. Cancer Cell 2018,
33, 125–136.e123. [CrossRef]
12. Schneider, M.A.; Eden, J.; Pache, B.; Laminger, F.; Lopez-Lopez, V.; Steffen, T.; Hubner, M.; Kober, F.; Roka, S.; Campos, P.C.; et al.
Mutations of RAS/RAF Proto-oncogenes Impair Survival After Cytoreductive Surgery and HIPEC for Peritoneal Metastasis of
Colorectal Origin. Ann. Surg. 2018, 268, 845–853. [CrossRef]
13. Zajac, O.; Raingeaud, J.; Libanje, F.; Lefebvre, C.; Sabino, D.; Martins, I.; Roy, P.; Benatar, C.; Canet-Jourdan, C.; Azorin, P.; et al.
Tumour spheres with inverted polarity drive the formation of peritoneal metastases in patients with hypermethylated colorectal
carcinomas. Nat. Cell Biol. 2018, 20, 296–306. [CrossRef]
14. Lemoine, L.; Sugarbaker, P.; Van der Speeten, K. Pathophysiology of colorectal peritoneal carcinomatosis: Role of the peritoneum.
World J. Gastroenterol. 2016, 22, 7692–7707. [CrossRef]
15. Kim, S.C.; Hong, C.W.; Jang, S.G.; Kim, Y.A.; Yoo, B.C.; Shin, Y.K.; Jeong, S.Y.; Ku, J.L.; Park, J.G. Establishment and Character-
ization of Paired Primary and Peritoneal Seeding Human Colorectal Cancer Cell Lines: Identification of Genes That Mediate
Metastatic Potential. Transl. Oncol. 2018, 11, 1232–1243. [CrossRef]
16. Moffitt, L.; Karimnia, N.; Stephens, A.; Bilandzic, M. Therapeutic Targeting of Collective Invasion in Ovarian Cancer. Int. J. Mol.
Sci. 2019, 20, 1466. [CrossRef]
17. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674. [CrossRef]
18. Hayashi, K.; Jiang, P.; Yamauchi, K.; Yamamoto, N.; Tsuchiya, H.; Tomita, K.; Moossa, A.R.; Bouvet, M.; Hoffman, R.M. Real-time
imaging of tumor-cell shedding and trafficking in lymphatic channels. Cancer Res. 2007, 67, 8223–8228. [CrossRef]
Cancers 2022, 14, 60 11 of 14

19. Mikula-Pietrasik, J.; Uruski, P.; Tykarski, A.; Ksiazek, K. The peritoneal “soil” for a cancerous “seed”: A comprehensive review of
the pathogenesis of intraperitoneal cancer metastases. Cell Mol. Life Sci. 2018, 75, 509–525. [CrossRef]
20. Saito, S.; Okabe, H.; Watanabe, M.; Ishimoto, T.; Iwatsuki, M.; Baba, Y.; Tanaka, Y.; Kurashige, J.; Miyamoto, Y.; Baba, H. CD44v6
expression is related to mesenchymal phenotype and poor prognosis in patients with colorectal cancer. Oncol. Rep. 2013, 29,
1570–1578. [CrossRef]
21. Gerber, S.A.; Rybalko, V.Y.; Bigelow, C.E.; Lugade, A.A.; Foster, T.H.; Frelinger, J.G.; Lord, E.M. Preferential attachment of
peritoneal tumor metastases to omental immune aggregates and possible role of a unique vascular microenvironment in
metastatic survival and growth. Am. J. Pathol. 2006, 169, 1739–1752. [CrossRef]
22. Heath, R.M.; Jayne, D.G.; O’Leary, R.; Morrison, E.E.; Guillou, P.J. Tumour-induced apoptosis in human mesothelial cells: A
mechanism of peritoneal invasion by Fas Ligand/Fas interaction. Br. J. Cancer 2004, 90, 1437–1442. [CrossRef]
23. Yao, J.F.; Li, X.J.; Yan, L.K.; He, S.; Zheng, J.B.; Wang, X.R.; Zhou, P.H.; Zhang, L.; Wei, G.B.; Sun, X.J. Role of HGF/c-Met in the
treatment of colorectal cancer with liver metastasis. J. Biochem. Mol. Toxicol. 2019, 33, e22316. [CrossRef]
24. Said, A.H.; Raufman, J.P.; Xie, G. The role of matrix metalloproteinases in colorectal cancer. Cancers 2014, 6, 366–375. [CrossRef]
25. Vocka, M.; Langer, D.; Fryba, V.; Petrtyl, J.; Hanus, T.; Kalousova, M.; Zima, T.; Petruzelka, L. Serum levels of TIMP-1 and MMP-7
as potential biomarkers in patients with metastatic colorectal cancer. Int. J. Biol. Markers 2019, 34, 292–301. [CrossRef]
26. Varghese, S.; Burness, M.; Xu, H.; Beresnev, T.; Pingpank, J.; Alexander, H.R. Site-specific gene expression profiles and novel
molecular prognostic factors in patients with lower gastrointestinal adenocarcinoma diffusely metastatic to liver or peritoneum.
Ann. Surg. Oncol. 2007, 14, 3460–3471. [CrossRef]
27. Fuchs, C.S.; Goldberg, R.M.; Sargent, D.J.; Meyerhardt, J.A.; Wolpin, B.M.; Green, E.M.; Pitot, H.C.; Pollak, M. Plasma insulin-like
growth factors, insulin-like binding protein-3, and outcome in metastatic colorectal cancer: Results from intergroup trial N9741.
Clin. Cancer Res. 2008, 14, 8263–8269. [CrossRef]
28. Dunn, G.P.; Old, L.J.; Schreiber, R.D. The three Es of cancer immunoediting. Ann. Rev. Immunol. 2004, 22, 329–360. [CrossRef]
[PubMed]
29. Dunn, G.P.; Bruce, A.T.; Ikeda, H.; Old, L.J.; Schreiber, R.D. Cancer immunoediting: From immunosurveillance to tumor escape.
Nat. Immunol. 2002, 3, 991–998. [CrossRef] [PubMed]
30. Chae, Y.K.; Arya, A.; Iams, W.; Cruz, M.R.; Chandra, S.; Choi, J.; Giles, F. Current landscape and future of dual anti-CTLA4 and
PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung
cancer (NSCLC). J. Immunother. Cancer 2018, 6, 39. [CrossRef] [PubMed]
31. Ogino, S.; Nosho, K.; Irahara, N.; Meyerhardt, J.A.; Baba, Y.; Shima, K.; Glickman, J.N.; Ferrone, C.R.; Mino-Kenudson, M.;
Tanaka, N.; et al. Lymphocytic reaction to colorectal cancer is associated with longer survival, independent of lymph node count,
microsatellite instability, and CpG island methylator phenotype. Clin. Cancer. Res. 2009, 15, 6412–6420. [CrossRef]
32. Merok, M.A.; Ahlquist, T.; Royrvik, E.C.; Tufteland, K.F.; Hektoen, M.; Sjo, O.H.; Mala, T.; Svindland, A.; Lothe, R.A.; Nesbakken,
A. Microsatellite instability has a positive prognostic impact on stage II colorectal cancer after complete resection: Results from a
large, consecutive Norwegian series. Ann. Oncol. 2013, 24, 1274–1282. [CrossRef]
33. Popat, S.; Hubner, R.; Houlston, R.S. Systematic review of microsatellite instability and colorectal cancer prognosis. J. Clin. Oncol.
2005, 23, 609–618. [CrossRef]
34. Jass, J.R.; Do, K.A.; Simms, L.A.; Iino, H.; Wynter, C.; Pillay, S.P.; Searle, J.; Radford-Smith, G.; Young, J.; Leggett, B. Morphology
of sporadic colorectal cancer with DNA replication errors. Gut 1998, 42, 673–679. [CrossRef]
35. Giannakis, M.; Mu, X.J.; Shukla, S.A.; Qian, Z.R.; Cohen, O.; Nishihara, R.; Bahl, S.; Cao, Y.; Amin-Mansour, A.; Yamauchi, M.;
et al. Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma. Cell Rep. 2016, 17, 1206. [CrossRef]
36. Peng, J.; Wang, Y.; Zhang, R.; Deng, Y.; Xiao, B.; Ou, Q.; Sui, Q.; Xu, J.; Qin, J.; Lin, J.; et al. Immune Cell Infiltration in the
Microenvironment of Liver Oligometastasis from Colorectal Cancer: Intratumoural CD8/CD3 Ratio Is a Valuable Prognostic
Index for Patients Undergoing Liver Metastasectomy. Cancers 2019, 11, 1922. [CrossRef]
37. Seebauer, C.T.; Brunner, S.; Glockzin, G.; Piso, P.; Ruemmele, P.; Schlitt, H.J.; Geissler, E.K.; Fichtner-Feigl, S.; Kesselring,
R. Peritoneal carcinomatosis of colorectal cancer is characterized by structural and functional reorganization of the tumor
microenvironment inducing senescence and proliferation arrest in cancer cells. Oncoimmunology 2016, 5, e1242543. [CrossRef]
38. Wang, R.; Song, S.; Harada, K.; Ghazanfari Amlashi, F.; Badgwell, B.; Pizzi, M.P.; Xu, Y.; Zhao, W.; Dong, X.; Jin, J.; et al. Multiplex
profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict
treatment response. Gut 2020, 69, 18–31. [CrossRef]
39. Sato, E.; Olson, S.H.; Ahn, J.; Bundy, B.; Nishikawa, H.; Qian, F.; Jungbluth, A.A.; Frosina, D.; Gnjatic, S.; Ambrosone, C.; et al.
Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable
prognosis in ovarian cancer. Proc. Natl. Acad. Sci. USA 2005, 102, 18538–18543. [CrossRef]
40. Auer, K.; Bachmayr-Heyda, A.; Aust, S.; Sukhbaatar, N.; Reiner, A.T.; Grimm, C.; Horvat, R.; Zeillinger, R.; Pils, D. Peritoneal
tumor spread in serous ovarian cancer-epithelial mesenchymal status and outcome. Oncotarget 2015, 6, 17261–17275. [CrossRef]
41. Auer, K.; Bachmayr-Heyda, A.; Sukhbaatar, N.; Aust, S.; Schmetterer, K.G.; Meier, S.M.; Gerner, C.; Grimm, C.; Horvat, R.; Pils, D.
Role of the immune system in the peritoneal tumor spread of high grade serous ovarian cancer. Oncotarget 2016, 7, 61336–61354.
[CrossRef] [PubMed]
Cancers 2022, 14, 60 12 of 14

42. Parvathareddy, S.K.; Siraj, A.K.; Al-Badawi, I.A.; Tulbah, A.; Al-Dayel, F.; Al-Kuraya, K.S. Differential expression of PD-L1
between primary and metastatic epithelial ovarian cancer and its clinico-pathological correlation. Sci. Rep. 2021, 11, 3750.
[CrossRef] [PubMed]
43. Sugarbaker, P.H. Surgical management of carcinomatosis from colorectal cancer. Clin. Colon Rectal Surg. 2005, 18, 190–203.
[CrossRef] [PubMed]
44. Neuwirth, M.G.; Alexander, H.R.; Karakousis, G.C. Then and now: Cytoreductive surgery with hyperthermic intraperitoneal
chemotherapy (HIPEC), a historical perspective. J. Gastrointest. Oncol. 2016, 7, 18–28. [CrossRef]
45. Jayne, D.G.; Fook, S.; Loi, C.; Seow-Choen, F. Peritoneal carcinomatosis from colorectal cancer. Br. J. Surg. 2002, 89, 1545–1550.
[CrossRef]
46. Franko, J.; Ibrahim, Z.; Gusani, N.J.; Holtzman, M.P.; Bartlett, D.L.; Zeh, H.J. Cytoreductive surgery and hyperthermic intraperi-
toneal chemoperfusion versus systemic chemotherapy alone for colorectal peritoneal carcinomatosis. Cancer 2010, 116, 3756–3762.
[CrossRef]
47. Munnell, E.W. The changing prognosis and treatment in cancer of the ovary. A report of 235 patients with primary ovarian
carcinoma 1952-1961. Am. J. Obstet. Gynecol. 1968, 100, 790–805. [CrossRef]
48. Munnell, E.W. Surgical treatment of ovarian carcinoma. Clin. Obstet. Gynecol. 1969, 12, 980–992. [CrossRef]
49. Griffiths, C.T.; Parker, L.M.; Fuller, A.F. Role of cytoreductive surgical treatment in the management of advanced ovarian cancer.
Cancer Treat Rep. 1979, 63, 235–240.
50. Long, R.T.; Spratt, J.S.; Dowling, E. Pseudomyxoma peritonei. New concepts in management with a report of seventeen patients.
Am. J. Surg. 1969, 117, 162–169. [CrossRef]
51. Dedrick, R.L.; Myers, C.E.; Bungay, P.M.; DeVita, V.T. Pharmacokinetic rationale for peritoneal drug administration in the
treatment of ovarian cancer. Cancer Treat Rep. 1978, 62, 1–11.
52. Sugarbaker, P.H. Peritonectomy procedures. Ann. Surg. 1995, 221, 29–42. [CrossRef]
53. Jacquet, P.; Sugarbaker, P.H. Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis.
Cancer Treat Res. 1996, 82, 359–374. [CrossRef]
54. Steffen, T.; Putora, P.M.; Hübner, M.; Gloor, B.; Lehmann, K.; Kettelhack, C.; Adamina, M.; Peterli, R.; Schmidt, J.; Ris, F.; et al.
Diagnostic Nodes of Patient Selection for Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Among
Colorectal Cancer Patients: A Swiss National Multicenter Survey. Clin. Colorectal. Cancer 2019, 18, e335–e342. [CrossRef]
55. Glehen, O.; Mohamed, F.; Gilly, F.N. Peritoneal carcinomatosis from digestive tract cancer: New management by cytoreductive
surgery and intraperitoneal chemohyperthermia. Lancet Oncol. 2004, 5, 219–228. [CrossRef]
56. Van’t Sant, I.; Engbersen, M.P.; Bhairosing, P.A.; Lambregts, D.M.J.; Beets-Tan, R.G.H.; van Driel, W.J.; Aalbers, A.G.J.; Kok, N.F.M.;
Lahaye, M.J. Diagnostic performance of imaging for the detection of peritoneal metastases: A meta-analysis. Eur. Radiol. 2020, 30,
3101–3112. [CrossRef]
57. Passot, G.; Dumont, F.; Goéré, D.; Arvieux, C.; Rousset, P.; Regimbeau, J.M.; Elias, D.; Villeneuve, L.; Glehen, O.; Group, B.-R.S.W.
Multicentre study of laparoscopic or open assessment of the peritoneal cancer index (BIG-RENAPE). Br. J. Surg. 2018, 105,
663–667. [CrossRef]
58. Elias, D.; Lefevre, J.H.; Chevalier, J.; Brouquet, A.; Marchal, F.; Classe, J.M.; Ferron, G.; Guilloit, J.M.; Meeus, P.; Goéré, D.;
et al. Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of
colorectal origin. J. Clin. Oncol. 2009, 27, 681–685. [CrossRef]
59. Quenet, F.; Elias, D.; Roca, L.; Goere, D.; Ghouti, L.; Pocard, M.; Facy, O.; Arvieux, C.; Lorimier, G.; Pezet, D.; et al. Cytoreductive
surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases
(PRODIGE 7): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021, 22, 256–266. [CrossRef]
60. Verwaal, V.J.; van Ruth, S.; de Bree, E.; van Sloothen, G.W.; van Tinteren, H.; Boot, H.; Zoetmulder, F.A. Randomized trial of
cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients
with peritoneal carcinomatosis of colorectal cancer. J. Clin. Oncol. 2003, 21, 3737–3743. [CrossRef]
61. Verwaal, V.J.; Bruin, S.; Boot, H.; van Slooten, G.; van Tinteren, H. 8-year follow-up of randomized trial: Cytoreduction and
hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy in patients with peritoneal carcinomatosis of colorectal
cancer. Ann. Surg. Oncol. 2008, 15, 2426–2432. [CrossRef] [PubMed]
62. Turaga, K.; Levine, E.; Barone, R.; Sticca, R.; Petrelli, N.; Lambert, L.; Nash, G.; Morse, M.; Adbel-Misih, R.; Alexander, H.R.;
et al. Consensus guidelines from The American Society of Peritoneal Surface Malignancies on standardizing the delivery of
hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer patients in the United States. Ann. Surg. Oncol. 2014, 21,
1501–1505. [CrossRef] [PubMed]
63. Yurttas, C.; Hoffmann, G.; Tolios, A.; Haen, S.P.; Schwab, M.; Königsrainer, I.; Königsrainer, A.; Beckert, S.; Löffler, M.W. Systematic
Review of Variations in Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Peritoneal Metastasis from Colorectal Cancer. J.
Clin. Med. 2018, 7, 567. [CrossRef] [PubMed]
64. Paz, M.M.; Zhang, X.; Lu, J.; Holmgren, A. A new mechanism of action for the anticancer drug mitomycin C: Mechanism-based
inhibition of thioredoxin reductase. Chem. Res. Toxicol. 2012, 25, 1502–1511. [CrossRef]
Cancers 2022, 14, 60 13 of 14

65. Arjona-Sánchez, A.; Barrios, P.; Boldo-Roda, E.; Camps, B.; Carrasco-Campos, J.; Concepción Martín, V.; García-Fadrique, A.;
Gutiérrez-Calvo, A.; Morales, R.; Ortega-Pérez, G.; et al. HIPECT4: Multicentre, randomized clinical trial to evaluate safety and
efficacy of Hyperthermic intra-peritoneal chemotherapy (HIPEC) with Mitomycin C used during surgery for treatment of locally
advanced colorectal carcinoma. BMC Cancer 2018, 18, 183. [CrossRef]
66. Schneider, M.A.; Eshmuminov, D.; Lehmann, K. Major Postoperative Complications Are a Risk Factor for Impaired Survival after
CRS/HIPEC. Ann. Surg. Oncol. 2017, 24, 2224–2232. [CrossRef]
67. Grass, F.; Vuagniaux, A.; Teixeira-Farinha, H.; Lehmann, K.; Demartines, N.; Hübner, M. Systematic review of pressurized
intraperitoneal aerosol chemotherapy for the treatment of advanced peritoneal carcinomatosis. Br. J. Surg. 2017, 104, 669–678.
[CrossRef]
68. Simkens, G.A.; van Oudheusden, T.R.; Luyer, M.D.; Nienhuijs, S.W.; Nieuwenhuijzen, G.A.; Rutten, H.J.; de Hingh, I.H.
Serious Postoperative Complications Affect Early Recurrence After Cytoreductive Surgery and HIPEC for Colorectal Peritoneal
Carcinomatosis. Ann. Surg. Oncol. 2015, 22, 2656–2662. [CrossRef]
69. Virzi, S.; Iusco, D.; Baratti, D.; Bonomi, S.; Grassi, A.; Kusamura, S.; Deraco, M. Pilot study of adjuvant hyperthermic intraperi-
toneal chemotherapy in patients with colorectal cancer at high risk for the development of peritoneal metastases. Tumori 2013, 99,
589–595. [CrossRef]
70. Klaver, C.E.L.; Wisselink, D.D.; Punt, C.J.A.; Snaebjornsson, P.; Crezee, J.; Aalbers, A.G.J.; Brandt, A.; Bremers, A.J.A.; Burger,
J.W.A.; Fabry, H.F.J.; et al. Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer
(COLOPEC): A multicentre, open-label, randomised trial. Lancet Gastroenterol. Hepatol. 2019, 4, 761–770. [CrossRef]
71. Gustavsson, B.; Carlsson, G.; Machover, D.; Petrelli, N.; Roth, A.; Schmoll, H.J.; Tveit, K.M.; Gibson, F. A review of the evolution
of systemic chemotherapy in the management of colorectal cancer. Clin. Colorectal. Cancer 2015, 14, 1–10. [CrossRef]
72. Loupakis, F.; Cremolini, C.; Masi, G.; Lonardi, S.; Zagonel, V.; Salvatore, L.; Cortesi, E.; Tomasello, G.; Ronzoni, M.; Spadi, R.;
et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N. Engl. J. Med. 2014, 371, 1609–1618.
[CrossRef]
73. Falcone, A.; Ricci, S.; Brunetti, I.; Pfanner, E.; Allegrini, G.; Barbara, C.; Crinò, L.; Benedetti, G.; Evangelista, W.; Fanchini, L.;
et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional
fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: The Gruppo Oncologico
Nord Ovest. J. Clin. Oncol. 2007, 25, 1670–1676. [CrossRef]
74. Cremolini, C.; Antoniotti, C.; Rossini, D.; Lonardi, S.; Loupakis, F.; Pietrantonio, F.; Bordonaro, R.; Latiano, T.P.; Tamburini,
E.; Santini, D.; et al. Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus
bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): A
multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020, 21, 497–507. [CrossRef]
75. Passot, G.; Vaudoyer, D.; Cotte, E.; You, B.; Isaac, S.; Noel Gilly, F.; Mohamed, F.; Glehen, O. Progression following neoadjuvant
systemic chemotherapy may not be a contraindication to a curative approach for colorectal carcinomatosis. Ann. Surg. 2012, 256,
125–129. [CrossRef]
76. Demtroder, C.; Solass, W.; Zieren, J.; Strumberg, D.; Giger-Pabst, U.; Reymond, M.A. Pressurized intraperitoneal aerosol
chemotherapy with oxaliplatin in colorectal peritoneal metastasis. Colorectal. Dis. 2016, 18, 364–371. [CrossRef]
77. Goere, D.; Glehen, O.; Quenet, F.; Guilloit, J.M.; Bereder, J.M.; Lorimier, G.; Thibaudeau, E.; Ghouti, L.; Pinto, A.; Tuech, J.J.;
et al. Second-look surgery plus hyperthermic intraperitoneal chemotherapy versus surveillance in patients at high risk of
developing colorectal peritoneal metastases (PROPHYLOCHIP-PRODIGE 15): A randomised, phase 3 study. Lancet Oncol. 2020,
21, 1147–1154. [CrossRef]
78. Solass, W.; Kerb, R.; Mürdter, T.; Giger-Pabst, U.; Strumberg, D.; Tempfer, C.; Zieren, J.; Schwab, M.; Reymond, M.A. Intraperi-
toneal chemotherapy of peritoneal carcinomatosis using pressurized aerosol as an alternative to liquid solution: First evidence for
efficacy. Ann. Surg. Oncol. 2014, 21, 553–559. [CrossRef]
79. Hollandsworth, H.M.; Turner, M.A.; Hoffman, R.M.; Bouvet, M. A review of tumor-specific fluorescence-guided surgery for
colorectal cancer. Surg. Oncol. 2021, 36, 84–90. [CrossRef]
80. Shariati, M.; Willaert, W.; Ceelen, W.; De Smedt, S.C.; Remaut, K. Aerosolization of Nanotherapeutics as a Newly Emerging
Treatment Regimen for Peritoneal Carcinomatosis. Cancers 2019, 11, 906. [CrossRef]
81. Luo, J.; Wu, Z.; Lu, Y.; Xiong, K.; Wen, Q.; Zhao, L.; Wang, B.; Gui, Y.; Fu, S. Intraperitoneal administration of biocompatible
hyaluronic acid hydrogel containing multi-chemotherapeutic agents for treatment of colorectal peritoneal carcinomatosis. Int J.
Biol. Macromol. 2020, 152, 718–726. [CrossRef]
82. Zhang, X.; Huang, H.; Yang, D.; Wang, P.; Huang, X.; Hu, Z.; Zhang, Y.; Yan, R.; Zhu, Z.; Cai, Q. Neoadjuvant Intraperitoneal
and Systemic Chemotherapy Versus Neoadjuvant Systemic Chemotherapy with Docetaxel, Oxaliplatin, and S-1 for Gastric
Cancer with Peritoneal Metastasis: A Propensity Score Matched Analysis. Technol. Cancer Res. Treat. 2021, 20, 15330338211036310.
[CrossRef]
83. Overman, M.J.; Lonardi, S.; Wong, K.Y.M.; Lenz, H.J.; Gelsomino, F.; Aglietta, M.; Morse, M.A.; Van Cutsem, E.; McDermott,
R.; Hill, A.; et al. Durable Clinical Benefit with Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite
Instability-High Metastatic Colorectal Cancer. J. Clin. Oncol. 2018, 36, 773–779. [CrossRef]
84. André, T.; Shiu, K.K.; Kim, T.W.; Jensen, B.V.; Jensen, L.H.; Punt, C.; Smith, D.; Garcia-Carbonero, R.; Benavides, M.; Gibbs, P.; et al.
Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N. Engl. J. Med. 2020, 383, 2207–2218. [CrossRef]
Cancers 2022, 14, 60 14 of 14

85. Matulonis, U.A.; Shapira-Frommer, R.; Santin, A.D.; Lisyanskaya, A.S.; Pignata, S.; Vergote, I.; Raspagliesi, F.; Sonke, G.S.; Birrer,
M.; Provencher, D.M.; et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer:
Results from the phase II KEYNOTE-100 study. Ann. Oncol. 2019, 30, 1080–1087. [CrossRef]
86. Tesniere, A.; Schlemmer, F.; Boige, V.; Kepp, O.; Martins, I.; Ghiringhelli, F.; Aymeric, L.; Michaud, M.; Apetoh, L.; Barault, L.; et al.
Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene 2010, 29, 482–491. [CrossRef]
87. Green, D.R.; Ferguson, T.; Zitvogel, L.; Kroemer, G. Immunogenic and tolerogenic cell death. Nat. Rev. Immunol. 2009, 9, 353–363.
[CrossRef]
88. Sharma, A.; Bode, B.; Wenger, R.H.; Lehmann, K.; Sartori, A.A.; Moch, H.; Knuth, A.; Boehmer, L.; Broek, M. gamma-Radiation
promotes immunological recognition of cancer cells through increased expression of cancer-testis antigens in vitro and in vivo.
PLoS ONE 2011, 6, e28217. [CrossRef]
89. Zunino, B.; Rubio-Patino, C.; Villa, E.; Meynet, O.; Proics, E.; Cornille, A.; Pommier, S.; Mondragon, L.; Chiche, J.; Bereder, J.M.;
et al. Hyperthermic intraperitoneal chemotherapy leads to an anticancer immune response via exposure of cell surface heat shock
protein 90. Oncogene 2016, 35, 261–268. [CrossRef]
90. Froysnes, I.S.; Andersson, Y.; Larsen, S.G.; Davidson, B.; Oien, J.T.; Olsen, K.H.; Giercksky, K.E.; Julsrud, L.; Fodstad, O.; Dueland,
S.; et al. Novel Treatment with Intraperitoneal MOC31PE Immunotoxin in Colorectal Peritoneal Metastasis: Results From the
ImmunoPeCa Phase 1 Trial. Ann. Surg. Oncol. 2017, 24, 1916–1922. [CrossRef]