Review

Challenges in the
multidisciplinary
management of stage IV
colon and rectal cancer
Expert Rev. Gastroenterol. Hepatol. 9(3), 317326 (2015)

Pompiliu Piso*1,
Dirk Arnold2 and
Gabriel Glockzin3
1
Department for General- and Visceral
Surgery, Hospital Barmherzige Brueder,
Pruefeninger Str. 86,
93049 Regensburg Germany
2
Department of Medical Oncology,
Tumor Biology Clinic, Albert Ludwigs
University, Freiburg, Germany
3
Department of Surgery, University
Hospital, Regensburg, Germany
*Author for correspondence:
Tel.: +49 941 369 2201
Fax: +49 941 369 2206
pompiliu.piso@barmherzige-regensburg.
de

Colorectal metastases still represent a challenge to all oncologists despite progresses

achieved by improved resectability, systemic chemotherapy and targeted therapies. In
particular in patients with oligo-metastases, the role of surgical resections has been
redefined. Resection is the most effective treatment method for liver metastases performed
with curative intent; however, primary rate of resectability is low. Several methods to
increase resectability have been developed: conversion chemotherapy, portal vein
embolization, two-stage resections, vascular reconstruction of the liver veins, combination
of resection and intraoperative ablation. Liver resections can be performed at present with
low mortality. Patients with isolated peritoneal metastases, no extra-abdominal disease,
low volume tumor and complete surgical cytoreduction do benefit from surgery and
hyperthermic intraperitoneal chemotherapy. Several national guidelines recommend
multimodality treatment for highly selected patients. The management of stage IV
colorectal cancer includes several disciplines with focus on resection. A multidisciplinary
evaluation of all patients is of crucial importance to define the treatment sequence and
individual strategies for each patient.
KEYWORDS: ALPPS HIPEC liver metastases peritoneal carcinomatosis

The treatment of colorectal metastases has

considerably changed over the last decades. On
the one hand, resection has shown improved
survival rate for liver metastases, with onethird of all patients alive 5 years after treatment; on the other hand, systemic therapies
including chemotherapy and targeted therapy
have continuously improved the median survival time up to 2428 months. Due to the
increased response rates, acceptable toxicity
and improved surgical techniques, more and
more patients, in particular those with oligometastases, are suitable for surgical procedures
with the aim of disease control and cure.
The present article focuses on the current
treatment strategies and future directions
for the most common metastatic sites of
advanced colorectal cancer (CRC): colorectal
liver metastases (CLM) and colorectal peritoneal metastasis (CPM).

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10.1586/17474124.2015.957273

Metastatic sites

The most frequent site of metastases for CRC

patients is the liver. The liver is the first filter
for tumor cells that are transported by the portal blood flow. The incidence of liver metastases, either synchronous or metachronous, is
about 20% [1]. The second site of metastases is
the peritoneum. The incidence is about 10%,
of which half is synchronous and half metachronous. One-third of the synchronous peritoneal metastases are diagnosed during surgery.
Small lesions cannot be diagnosed by staging
CT scan as the sensitivity for lesions smaller
than 5 mm is very low. The mechanism of
peritoneal dissemination is still not clear; however, free intraperitoneal tumor cells may have
the most important contribution to the tumor
spread [2]. Lung metastases are rare and have
an incidence of about 5%. Other rare sites are

2014 Informa UK Ltd

ISSN 1747-4124

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distant lymph node peritoneal metastases, skeleton metastases

or brain metastases. In some cases, metastases can be diagnosed
simultaneously at several sites, making the treatment strategies
more difficult.
Liver metastases
Resection as first choice of treatment in a multidisciplinary
setting

A report on large retrospective series of patients with resected

liver metastases changed the treatment strategy about two
decades ago. The published data from Hughes et al. showed
in 859 patients treated in 24 US institutions a 4-year survival
rate of 33% after complete resection of liver metastases [3].
In a large series of 1718 patients with colorectal metastases,
Scheele et al. later showed a resection rate of 25% and a 5-year
survival rate of 39% following liver resection [4]. Moreover, a
large series of 1001 consecutive patients undergoing liver resection demonstrated a survival rate of 37% at 5 years. This
report had two important messages. First, mortality of 2.8%
was low, showing that liver resections can be performed safely
and second, the Fong score was described. This includes five
parameters: node positivity of the primary, disease-free interval
from primary to metastases, number of hepatic tumors, largest
hepatic tumor and the carcinoembryonic antigen level (each
criterion was assigned with one point). No patient with a score
of 5 was a long-term survivor [5]. Over the last decade, several
other studies on results of liver resections for colorectal metastases have been published. More recently, a meta-analysis of
86 studies reported a median 5-year survival rate after resection
of 38% with a range of 16 to 74% [6]. Around 20% of all
patients can be cured as shown in a meta-analysis performed
by Abbas et al. Based on these data, several national and international guidelines recommend the resection of liver metastases
as the first-choice treatment method in patients suitable for surgery, showing 10-year survival rates from 12 to 36% [7]. The
increased use of hepatic resections, and more recently due to
advancements in medical therapy, had a profound impact on
the survival of patients with CLM with considerable improvement of treated patients [8]. This shift in survival is real and
published across many countries and different patient series,
changing the standard of treatment for patients with liver
metastases.

For the decision of whether to resect or not, two categories

of factors play a role: first, the surgical technical resectability
and second, the oncologic criteria.
To define resectability on standardized criteria is rather difficult as there is considerable individual variability, even between
experts, in particular for borderline resectable metastases. This
was evident lately during the CELIM study, showing that in
this special group of patients one-third of all experts have a different opinion of what represents resectable lesions [9]. Basically,
the decision is difficult mainly due to two reasons. One is the
proximity of large blood vessels with possible infiltration, in
particular of the liver veins. The other is the volume of the
liver remnant. This can be determined by volumetry; however,
the functionality of the hepatic tissue is difficult to assess, even
with liver functional test, for example, LiMax test.
Surgical procedures & resection types

Most frequent performed types of liver resections are so-called

atypical or subsegmental resections. With an adequate resection
margin, the liver parenchyma is transected and sealed with different techniques, mostly by CUSA dissector and clip application. Atypical resections, sometimes anatomical segmental
resections, have the advantage of sparing parenchyma enabling
further resections for later recurrences with no negative impact
on prognosis. Sometimes, in particular for multiple and bilateral metastases, anatomic resections with lobectomies or trisegmentectomies have to be performed.
Liver resections can be performed at present with low morbidity and low mortality, the blood loss during major procedures is very low and routine liver resections can be performed
without any blood transfusion. This had increased the acceptance of liver resection within the oncologic community. Further techniques as laparoscopic or robotic liver surgery for
metastases are now performed in specialized centers and are
able to further reduce the postoperative morbidity. In a recent
matched pair analysis, Montalti et al. show advantages of laparoscopic liver resections in terms of reduced blood loss, morbidity rate and hospital stay with comparable long-term results
when compared to open procedures [10]. Altogether, the progresses in liver surgery have been considerable over the last two
decades and enable surgical oncologist to offer up to half of all
patients with liver metastases the option of a R0 resection.

Resectability

Strategies to increase resectability

For many years, the number, size or the location of metastases

in both liver lobes represented a contraindication for surgery.
Extrahepatic tumor manifestations have also been considered to
be absolute contraindications. At present, these factors may
have a prognostic impact; however, if an R0 resection can be
achieved, an operation is indicated. Therefore, for the final
decision regarding surgical option, the adequate liver remnant
plays a more important role than the tumor mass to be
resected. Most experts agree that 30% of the initial liver volume is sufficient to avoid postoperative liver failure.

Considering all primary resections of liver metastases, the resection rate is only 1520%; therefore strategies to increase resectability are necessary. Some have been proven to be effective
alone or in combination of different procedures. These will be
described next (BOX 1).

318

Conversion chemotherapy

For the conversion, very active treatment regimens are necessary

to achieve a maximal response rate. Therefore, the combination
of several chemotherapeutic and targeted agents is recommendable. With an effective regimen, the secondary resection rate
Expert Rev. Gastroenterol. Hepatol. 9(3), (2015)

Challenges in the multidisciplinary management of stage IV colon & rectal cancer

can be as high as 20%, with long-term survival rates similar to

those after primary resection of liver metastases. As during chemotherapy side effects of the chemotherapy may alter the liver
parenchyma, the treatment duration has to be limited in order
to reduce the postoperative complications rate. Most frequent
side effects are oxaliplatin-induced sinusoidal obstruction with
blue liver syndrome and steatohepatitis induced by irinotecan.
The number of cycles should be lower than 9, if possible even
6 to keep the morbidity low [11]. Increasing the number of
cycles not only deteriorates the parenchyma, it also not increases
the rate of pathologic responses. Therefore, close monitoring of
the metastases during treatment is recommendable to be able to
detect resectable lesions in time and plan the liver resection.
Treating with the aim of maximal response is not reasonable,
not only due to possible morbidity but also because some of the
lesions will not be detectable anymore and may cause recurrences as complete pathologic remissions are very seldom [12].
One possible method to increase secondary resectability rate
is the addition of hepatic artery chemotherapy to the systemic
one. At least in the large experience of the Memorial group
from New York, 25% of all 373 investigated patients with irresectable metastases responded sufficiently to undergo resection
and ablation for cure [13].
Another option to intensify the induction chemotherapy is
the addition of several drugs in combination with targeted therapy. In a study published by Falcone et al., the combination of
FOLFOXIRI and bevacizumab produced high rates of pathologic response (63%) and necrosis (52% had more than 50%
necrotic areas) [14].
Challenging is the disappearance of metastases after systemic
chemotherapy. Despite non-visibility in the CT scans, a residual microscopic disease is found in 2545% of the patients,
suggesting that resection should later include all original sites
of disease if possible, as reported in a review published by
Bischof et al. [15].
Portal vein embolization

To increase the volume of the liver remnant, the embolization of

the portal venous system of the liver lobe to be resected can be
performed, at present mostly by interventional radiologists. To
induce an adequate hypertrophy, it is important to embolize
selective also the segment IV branches for a planned trisegmentectomy. In a meta-analysis including more than 1000 patients,
85% of all patients could be resected 46 weeks following embolization with a very low complication rate related directly to the
portal embolization [16]. Therefore, many departments dedicated
to liver surgery are using this method, being able to reduce the
risk of liver failure after extended liver resections. However, it is
not predictable how good a liver will regenerate as it depends on
the quality of liver parenchyma and factors such as steatosis, jaundice, alterations due to chemotherapy and others.
Two-stage resection

For bilateral metastases due to the small potential liver remnant, the resection has to be timed in two different sequential
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Review

Box 1. Strategies to increase respectability for liver

metastases of colorectal cancer.
Conversion chemotherapy
Portal vein embolization
Two-stage resection including ALPPS
Vascular reconstruction including ante- and ex-situ resections
Intraoperative ablation
Liver first strategies

operations. Most frequent, the future remnant is cured of tumor

by atypical resection of all metastases combined with a portal
ligation/transection of the portal vein branch to the liver lobe to
be resected during the second operation. Between the two procedures, the hypertrophy enables a lobectomy/trisegmentectomy
in order to achieve a tumor-free liver. As shown in a systematic
review by Chua et al., 77% of all patients do complete both procedures, however, with the price of an increased morbidity. The
median survival is 37 months [17].
The problem with the portal vein resection is the insufficient
hypertrophy, in particular if segment IV branches were not
embolized. Moreover, 4 to 6 weeks are necessary until a significant increase in volume can be detected. Therefore, a new surgical technique has been described. In this procedure, the liver
parenchyma is transected in combination with the portal vein
branch ligation and transection, similar to living donor split
transplantation, mostly medialy from the segments II and III.
About 9 days later, the liver resection is completed. The procedure is called associating liver partition and portal vein ligation
for staged hepatectomy associated with high morbidity and yet
unknown oncologic results (FIGURES 1 & 2). However, it enables
resection in patients considered otherwise irresectable, mainly
due to a hypertrophy rate of the future remnant liver of
44200%. Due to the special technique and still missing longterm results, associating liver partition and portal vein ligation
for staged hepatectomy should be an option only for a
restricted and well-selected subgroup of patients [18].
Vascular reconstruction including ante- & ex-situ resections

In some cases, the vascular tumor infiltration is the cause of

irresectability because all three liver veins are involved. Resection of infiltrated liver artery is of questionable oncological
benefit and seldom necessary. Therefore, intrahepatic infiltration of liver veins is the main issue to be addressed. Even following conversion chemotherapy, resection may not be feasible.
In this situation, only a vascular resection with reconstruction
can help. It may be a rather easy one, for example, with segmental resection of the right, middle or left liver vein next to
the vena cava, but it may be as complex as an ante- or ex-situ
resection. In this case, the portal vein has to be perfused, similar to living donation for transplant operations, while the blood
of the lower extremities is transported via bypass procedure
into the axillary veins. The tumor is removed, vessels reconstructed and the liver re-perfused. However, this procedure is
very seldom, and only few centers worldwide perform it [19].
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randomized studies are still ongoing [22]. These have to be

awaited as there is some controversy that the resection of the
primary may confer some survival advantage in stage IV.
Resection combined with perioperative chemotherapy

Figure 1. The in-situ split of the liver as a first step of first

step of ALPPS combined with the combined with the
(A) portal vein transection followed by (B) trisegmentectomy
with a liver remnant including segments II and III.

Intraoperative ablation

Due to focused specialization, many interventional radiologists

treat liver metastases percutaneousely, either using radiofrequency, or microwave or recently irreversible electroporation [20].
However, the procedure is associated with rather high recurrent
rate in particular for metastases having a diameter of more than
5 cm. Therefore, it is ideal for lesions smaller than 2 cm, and
the combination with resection may be an option for lesions
that are situated central in the liver remnant, not suitable for
further resection. The advantage of combining the procedures
is the ultrasound guidance having the option of moving the
liver manually and the vascular occlusion for lesions situated in
vascular proximity. The combination with vascular exclusion is
feasible as demonstrated by Evrard et al. in a study including
358 patients. The metastases had a median size of 2 cm, and
no recurrences were observed (FIGURE 3) [21].
Liver first strategies & resection of the primary tumor

Some patients with synchronous liver metastases have bilateral

lesions and a colorectal tumor not causing obstruction or bleeding. Operating the primary in this situation may cause a delay
in the effective systemic treatment with chemotherapy and targeted agents, in particular if the postoperative course is complicated. Therefore, treating the liver first is reasonable as it will
mainly determine the prognosis of those patients. Chemotherapy is then followed by liver resection and finally, in further
procedure, by the resection of the primary. This strategy has
been proven in few studies to be feasible. A recent systematic
review showed the feasibility of this sequence; however,
A

Figure 2. A significant volume increase of the future liver

remnant can be seen. (A) Preoperative and (B) postoperative
volumetry of the liver remnant after associating liver partition
and portal vein ligation for staged hepatectomy.

320

There is not much data on the effect of perioperative chemotherapy in resectable liver metastases. Best data originate from
the EORTC 40983 trial published by Nordlinger et al. In this
prospective randomized trial 364 patients have been randomized to either resection alone or with perioperative systemic
chemotherapy with FOLFOX. The overall survival (OS) was
not different; however, the progression-free survival was better
in the chemotherapy arm; therefore the authors recommended
the combined treatment [23].
Resection in patients with liver metastases & extrahepatic disease

In patients with liver and lung metastases, resection may lead

to long-term survival if all visible disease has been removed.
However, the evidence is from non-controlled studies, and the
results have a large range of 974% 5-year survival rate as
shown in a review article by Gallinger et al. [24].
For patients with liver metastases and peritoneal carcinomatosis, the combined resection including hyperthermic intraperitoneal chemotherapy may be of benefit for selected patients
with limited disease, mostly maximum three peripheral and
resectable liver metastases, as shown in a rather small patients
group by Elias et al. [25].
Palliative chemotherapy

There are many regimens that can be given to patients with

definitive irrresectable metastases. Provided that they have
symptoms and a good general condition, intensive treatment
regimens combining systemic chemotherapy, mainly FOLFOX
or FOLFIRI, with monoclonal antibodies, for example, bevacizumab, cetuximab, panitumumab. Recently alfibercept and
regorafinib have completed the therapeutic arsenal. Basically, in
most patients with RAS wild type, an EGFR antibody is of
first preference. The FIRE-3 study showed better OS for
patients treated by FOLFIRI and cetuximab compared to bevacizumab [26]. For mutated RAS patients, VEGF antibodies still
represent first option. However, there are some head-to-head
comparison trials ongoing; therefore, their results have to
be awaited.
Peritoneal metastases
Natural history

CPM are common in patients with advanced CRC or disease

recurrence. They are caused by free intra-abdominal tumor
cells [27]. Approximately 10% of patients already show peritoneal tumor deposits at the time of initial diagnosis. In at least
25% of these patients with CPM, the peritoneal spread is the
only site of metastasis [28]. Moreover, about every fourth
patient with CRC develops peritoneal metastasis during the
course of disease [29]. However, in most patients, peritoneal
tumor dissemination is associated with poor prognosis. In the
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Challenges in the multidisciplinary management of stage IV colon & rectal cancer

Review

European multicenter EVOCAPE I, patients with peritoneal

metastatic CRC (pmCRC, n = 118) reached a median OS rate
of 5.2 months [30]. Several scores have been developed to classify the extent of intra-abdominal tumor dissemination and to
predict the oncological outcome of patients with pmCRC.
Recently developed scoring systems such as the peritoneal surface disease severity score or the colorectal peritoneal score that
integrated histologic features and patient-related factors may be
helpful to predict patient outcome and select patients for different therapeutic approaches [31,32]. However, the most commonly used classification system for peritoneal metastasis is the
peritoneal cancer index (PCI) that describes the size and tumor
distribution pattern in 13 abdominal regions leading to a score
ranging from 0 to 39 [33]. In principle, increasing PCI correlates with decreasing survival rates.
Systemic chemotherapy for peritoneal metastases

Peritoneal metastases differ from other organ or lymphatic

metastases. They tend to build avascular tumor nodules and
therefore limit the efficacy of systemic chemotherapy [34]. By
analyzing a subgroup of 364 patients with pmCRC out of
2095 patients enrolled in the two prospective randomized
NCCTG Phase III trials N9741 and N9841, Franko et al.
showed a 30% relative reduction of OS in case of peritoneal
metastases. The 5-year OS rates were 4.1 versus 6% and the
median survival was 12.7 months in the pmCRC group versus
17.6 months in the non-pmCRC group. In this analysis, infusional oxaliplatin-based chemotherapy was superior to irinotecan in first-line therapy irrespective of the peritoneal metastasis
status [35]. Klaver et al. analyzed the patients with pmCRC
enrolled in the prospective randomized CAIRO and
CAIRO2 trial. The median OS significantly decreased in both
trials in case of the presence of peritoneal metastasis and
reached 10.4 versus 17.3 months in the CAIRO trial and
15.2 versus 20.7 months in the CAIRO2 trial, respectively [36].
French registry data from 63 patients that received different
regimens of modern systemic chemotherapy showed a median
OS of 23.9 months [37]. An Asian prospective single-arm
Phase II study investigating FOLFOX-4 in patients with peritoneal metastases from CRC reported a median time to progression of 4.4 months and a median OS of 21.5 months [38].
Although peritoneal metastasis, in principle, leads to an
impairment of the oncological outcome, published data show
that modern systemic chemotherapy significantly improves survival in comparison to the natural course of disease. Thus, systemic chemotherapy should build the backbone of an
interdisciplinary multimodal treatment regimen for patients
with CPM. In the absence of contraindications, oxaliplatinbased regimens might be preferred as first-line therapy in
these patients.
Cytoreductive surgery

As described by Sugarbaker et al. cytoreductive surgery (CRS)

may consist of numerous peritonectomy procedures and visceral resections to allow for removal of all visible tumor
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Figure 3. Intraoperative radiofrequency ablation for

residual liver metastases after extended liver resection.

deposits within the abdominal cavity [39]. Moran et al.

defined five main categories of surgical procedures during CRS
(FIGURES 46 & BOX 2) [40]. The extent of surgery is related to the
affected areas of the peritoneal cavity. Only these have to be
resected. In patients with low-volume disease, the operation
may be limited, for example, right colectomy with partial parietal peritonectomy and omentectomy for a local advanced cecal
tumor. However, in high-volume disease patients, parietal and
visceral peritonectomy will include multivisceral resections.
These operations are time consuming and combined with high
morbidity and, however, with low mortality in experienced
centers. The number of centers is increasing every year, as
reports from numerous institutions worldwide are published on
regularly basis.
The success of surgery is classified according to the completeness of cytoreduction (CC) score that is based on the size
of residual tumor deposits and highly correlated with the oncological outcome [41,42]. A complete macroscopic cytoreduction
(CC-0/1), defined as no visible tumor or single tumor nodules

Figure 4. Preoperative CT scan (A) showing peritoneal

metastases and ascites in a patient with peritoneal
metastases from a mucinous appendix cancer in the upper
abdomen needing cytoreduction including splenectomy,
subtotal gastrectomy and (B) parietal peritonectomy in the
same patient.

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A

Piso, Arnold & Glockzin

additional peritonectomy procedures and HIPEC might be

considered in patients with CLM and limited CPM. Combined extensive liver surgery and extensive CRS should be
avoided. However, consistent preoperative patient selection and
intraoperative decision-making is crucial for patient outcome
regarding survival and quality of life.

Hyperthermic intraperitoneal chemotherapy

Figure 5. Preoperative CT scan (A) showing peritoneal

metastases in a patient with peritoneal metastases behind
the liver and (B) intraoperative view following resection.

<2.5 mm, should be obtained as a precondition for the efficient

application of hyperthermic intraperitoneal chemotherapy
(HIPEC). Thus, complete exploration of the abdominal cavity
and precise determination of intraoperative PCI is mandatory.
Therefore complete midline incision should be the standard
approach for CRS. Nevertheless, there might be a role for laparoscopic CRS in highly selected patients with limited peritoneal
metastasis and non-aggressive disease such as low-grade pseudomyxoma peritonei [43,44]. Due to the limitations regarding
exploration and resection, the laparoscopic approach cannot be
recommended for patients with pmCRC.
Limited data are published regarding surgical treatment of
combined colorectal peritoneal and liver metastasis. Due to the
Milan consensus statement of the Peritoneal Surface Malignancy Group International , more than three peripheral resectable liver metastases should be considered to be a relative
contraindication for CRS and HIPEC [45]. However, two retrospective studies with limited numbers of patients showed
median survival rates of about 36 months after CRS including
mostly minor liver resections and HIPEC [46,47]. Allard et al.
published a median survival of 42 months in patients that
underwent complete resection of CLM and unexpected limited
CPM with a median PCI of 2 [48]. In a retrospective matchedpair analysis, we could show that hepatobiliary procedures during CRS and HIPEC do not seem to increase morbidity and
mortality rates [49]. Thus, additional liver resection might be
considered in patients with CPM and limited CLM as well as
A

Figure 6. Preoperative CT scan (A) showing peritoneal

metastases in a patient with peritoneal metastases from a
mucinous appendix cancer in the lower abdomen with
cytoreduction including resection of the rectosigmoid and
lower abdomen with cytoreduction (B) including resection
of the rectosigoid and parietal peritonectomy.

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The aim of intraoperative HIPEC after CC-0/1 as an integrative part of the combined treatment regimen is the maintenance of the complete surgical tumor resection by destroying
scattered and residual tumor cells within the abdominal cavity.
The prospective randomized Dutch trial could show that the
addition of CRS and HIPEC to systemic chemotherapy leads
to a significant survival benefit in selected patients with
pmCRC. The median survival was 22 months after CRS and
HIPEC followed by systemic chemotherapy with 5-FU versus
12.6 months in the control group with 5-FU-based systemic
chemotherapy only. In the subgroup analysis of patients after
CC-0/1, median survival increased to 42.9 months [50,51].
Elias et al. reported a median survival of 62.7 months and a
5-year survival rate of 51% after CC-0/1 and bidirectional
oxaliplatin-based HIPEC [37]. The same HIPEC regimen was
used in a prospective Phase II study, leading to a 2-year OS
rate of 88.7% and a median disease-free survival (DFS) of
19.8 months [52]. The addition of intraperitoneal irinotecan
increased morbidity but could not further improve survival.
Quenet et al. reported a median OS 47 months and a 5-year
survival rate of 42.4% [53]. In a recently published analysis of
107 patients with a median follow-up of 77 months, a cure
rate, defined as 5-year survival without evidence of disease, of
16% was observed [54]. Nevertheless, the exact role of HIPEC
within the interdisciplinary multimodal treatment concept, the
treatment regimen regarding drugs, duration and technique
and its contribution to overall morbidity is still a matter of
debate. In a comparative analysis published by Hompes et al.,
there was no statistically significant difference regarding median
recurrence-free or OS between bidirectional oxaliplatin-based
HIPEC and MMC-based HIPEC after complete macroscopic
cytoreduction. Median recurrence-free was 12.2 months in the
oxaliplatin group and 13.8 months in the MMC group, respectively (p = 0.87). Median OS was 37.1 months versus
26.5 months (p = 0.45) [55]. A matched-pair analysis showed
no significant differences regarding morbidity and mortality
depending on the HIPEC regimen. The grade 3/4 morbidity
rates according to CTCAE were 42.5% in the OX group
versus 37.5% in the MMC group (p = 0.648) and the mortality rates 2.5 versus 0% [56]. In a systematic review of the published morbidity and mortality after CRS and HIPEC of
24 international peritoneal surface malignancies centers, the
mean morbidity rate was 28.8% (range 052) and the mean
mortality rate 2.9% (range 017) [57]. Interestingly, Shen et al.
showed no significant differences regarding morbidity, mortality and OS between patients after complete resection of CLM
and patients after complete CRS and HIPEC for CPM [58].
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Challenges in the multidisciplinary management of stage IV colon & rectal cancer

In conclusion, CRS and HIPEC can be performed with low

mortality and acceptable morbidity in specialized treatment
centers and should be considered as an additional standard
therapeutic option within a multidisciplinary treatment concept
for selected patients with pmCRC. Nevertheless, further prospective randomized trials are necessary to define the role of
HIPEC and its components within the combined treatment
concept and optimize standardized HIPEC regimens.

Review

Box 2. Parietal and visceral peritonectomy procedures as described by Sugarbaker and modified by
Moran [39,40].
Right hemicolectomy, omentectomy, splenectomy
Peritonectomy right and left upper quadrant
Cholecystectomy, resection of Glissons capsule
(Subtotal) gastrectomy
Anterior rectal resection and pelvic peritonectomy

Perioperative chemotherapy combined with surgical

cytoreduction & regional chemotherapy

Postoperative systemic chemotherapy was shown to be an independent positive prognostic marker in all registries and retrospective analyses [42,59]. Nevertheless, the optimal sequence of
systemic therapy and surgery is not defined. In the retrospective
analysis published by Elias et al., neoadjuvant systemic chemotherapy had no significant impact on prognosis of patients that
underwent CRS and HIPEC for CPM [42]. Passot et al. analyzed
90 patients with CPM that received neoadjuvant chemotherapy
before CRS and HIPEC. The response rate was 36%, whereas
21% of patients showed progressive disease. Interestingly,
response to neoadjuvant treatment was no significant prognostic
factor. The median survival of patients with disease progression
was 31.4 months. In the univariate analysis, neoadjuvant treatment was a positive prognostic factor (p = 0.042) [60]. Thus, progression during preoperative chemotherapy might not be
considered to be an absolute contraindication for CRS and
HIPEC. Recently published response rates on different preoperative chemotherapy regimens consisting of 5-FU, oxaliplatin, irinotecan and/or monoclonal antibodies of 115 patients with
CPM showed the following results: 9.7% complete response,
20.2% major response and 70.1% minor or no response. In the
multivariate analysis, pathohistological response was an independent predictor of survival (p = 0.01) [61]. These results show that
response can be achieved by preoperative systemic chemotherapy
in patients with CPM and may support perioperative treatment
regimens. There is an ongoing Phase II study evaluating CRS
and HIPEC with perioperative cetuximab-containing chemotherapy. Survival data of the COMBATAC trial are not yet available [62]. However, prospective randomized trials focused on
patients with CPM are necessary to optimize the multimodal
treatment regimens.

Other: pancreatic tail resection, hysterectomy, small-bowel

segmental resection, urinary bladder resection

NHS/NICE recommendation in The United Kingdom and the

German S3-guideline for CRC with major impact for the daily
practice [63,64]. This changed already the awareness regarding
this therapeutic option, as many cases are now systematically
analyzed in tumourboards. Basically, the recommendation for
CRS and HIPEC is reserved for patients with isolated peritoneal metastases with low tumor volume, no extra-abdominal
disease, in whom a CC-0/1 is achievable. In centers with expertise the procedure can be performed with low mortality.
However, many other countries still consider this procedure
experimental, for example, in the USA although many centers
offer this treatment for thousands of patients.
Expert commentary & five-year view

The treatment of colorectal metastases will further changed

over the next years. Improved surgical techniques will lead to
increased resection rates. Systemic therapy including chemotherapy and targeted therapy will improve and get more individualized based on molecular profiles of each patient. The
median survival will get over 3 years with higher response rates
and lower toxicity. More patients with isolated organ metastases
and good general condition will be suitable for resection as surgical procedures will be performed with low mortality and in
selected cases by minimal invasive route. The combination of
different strategies, as indicated, will increase the resectability
for liver metastases, enabling resection rates of 6070%. Peritoneal metastases will be detected and treated at an earlier stage
in many patients and patients at risk, for example, perforated
tumors, will be treated proactive in order to reduce the incidence of peritoneal metastases. The aim will be to control the
disease and re-operate on recurrence in time.

Guidelines

Due to the convincing results for selected patients with CRC

and peritoneal metastases, some guidelines have adopted the
recommendation toward multimodality treatment in these
patients, including cytoreduction and regional chemotherapy.
The first one was the French guideline in 2008. It was the
result of a consensus between the French society of digestive
surgery and a group of oncologists and gastroenterologists.
Regional scientific groups in the Netherlands, Spain and Italy
adopted similar guidelines. However, 2013 followed the

informahealthcare.com

Financial & competing interests disclosure

P Piso has received honoraria from Roche and Merck Serono. D Arnold
has received research grants from Roche and Sanofi and honoraria from
Roche, Sanofi, Merck Serono, Amgen and Bayer. The authors have no
other relevant affiliations or financial involvement with any organization
or entity with a financial interest in or financial conflict with the subject
matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this
manuscript.

323

Review

Piso, Arnold & Glockzin

Key issues
Resection is the most effective method to treat liver metastases; however, primary resectability is still rather low.
Several methods to increase resectability are available: conversion chemotherapy, portal vein embolization, two-stage resections, vascular
reconstruction of the liver veins, combination of resection and intraoperative ablation.
During conversion chemotherapy, patients have to undergo resection within the first 3 months of treatment. After that, further
response is minimal but perioperative morbidity high.
Liver resections can be performed at present with low mortality and in specialized centers by minimal invasive routes.
The continuous (re)interdisciplinary evaluation of all patients with liver metastases is of crucial importance.
Selected patients with peritoneal metastases may benefit from cytoreductive surgery and hyperthermic intraperitoneal chemotherapy
Selection criteria are isolated peritoneal metastases with no extra-abdominal disease, low-volume tumor and complete surgical
cytoreduction.

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