Expert Review of Anticancer Therapy

ISSN: 1473-7140 (Print) 1744-8328 (Online) Journal homepage: http://www.tandfonline.com/loi/iery20

Applications of hyperthermic intraperitoneal

chemotherapy for metastatic colorectal cancer

Matthias Hornung, Jens M. Werner & Hans J. Schlitt

To cite this article: Matthias Hornung, Jens M. Werner & Hans J. Schlitt (2017): Applications of
hyperthermic intraperitoneal chemotherapy for metastatic colorectal cancer, Expert Review of
Anticancer Therapy, DOI: 10.1080/14737140.2017.1357470

To link to this article: http://dx.doi.org/10.1080/14737140.2017.1357470

Accepted author version posted online: 18

Jul 2017.

Submit your article to this journal

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=iery20

Download by: [Cornell University Library] Date: 20 July 2017, At: 00:07
Publisher: Taylor & Francis

Journal: Expert Review of Anticancer Therapy

DOI: 10.1080/14737140.2017.1357470
Review

Applications of hyperthermic intraperitoneal chemotherapy

for metastatic colorectal cancer

Matthias Hornung1, Jens M. Werner1 and Hans J. Schlitt1*

1
University of Regensburg, Regensburg, Germany

*Corresponding author:

Hans J. Schlitt

University of Regensburg,

Regensburg,

Germany

Email: hans.schlitt@ukr.de
Abstract

Introduction: Cytoreductive surgery (CRS) combined with hyperthermic

intraperitoneal chemotherapy (HIPEC) plays a pivotal role in the current treatment of
peritoneal carcinomatosis (PC) from colorectal cancer (CRC). Since the first
demonstration, benefits for patients and especially an increase in survival have been
described. In recent years, feasibility, efficacy and safety of HIPEC have been
improved and progress has been made in understanding its oncological mechanism.

Areas Covered: In this article, leading publications have been reviewed including
clinical trials to describe the clinical presentation of PC due to CRC and present
recent evidence of the CRS/HIPEC procedure. The surgical approach including
evaluation of the extent of PC is described and, in addition, the article reports about
different HIPEC techniques as well as several protocols. Furthermore, the
development and prognostic benefit of the combination of intraperitoneal and
intravenous chemotherapy are outlined. Consideration has been given in particular to
patient selection and the use of HIPEC if complete cytoreduction is not feasible.

Expert Commentary: The CRS/HIPEC procedure represents a curative approach to

treat patients with PC from CRC. However, surgical skills and the HIPEC technique
still require specialized oncological centers.

Keywords: Colorectal cancer, Peritoneal carcinomatosis, Cytoreductive surgery,

Hyperthermic intraperitoneal chemotherapy, Bidirectional chemotherapy.
1. Introduction
Metastatic tumor spread into the peritoneal cavity, also called peritoneal
carcinomatosis (PC), occurs in up to 28% of patients suffering from colorectal cancer
(CRC).(1) Receiving no treatment, these patients have an average survival time of
about six months. (2;3) Peritoneal carcinomatosis can be divided into synchronous
and metachronous appearance. Notably, in both forms about 60% of the patients are
free of systemic metastases.(4) Even in recurrent CRC it seems that in 25% of the
patients the peritoneal cavity represents the only site of metastasis(2;5).

There are two pathophysiologically distinct routes tumor cells could spread into the
abdominal cavity. Either preoperative through direct cancer invasion of the whole
thickness of the intestinal wall or during surgical resection due to rupture of lymph
and blood vessels or the tumor itself.(6)

Likewise, several independent risk factors for the development of PC have been
described such as pT4 tumor stage (tumor invading the serosa layer or adjacent
organs), age over 59 and increased CA19-9. (7;8) A large systematic review of
literature indicate that synchronous PC, synchronous isolated ovarian metastases
and a perforated primary tumor could increase the risk of recurrent PC after curative
surgery.(9)

Furthermore, several studies tried to analyze peritoneal seeding of tumor cells

especially originated form colon cancer. Tumor cells were collected prior to resection
either through peritoneal lavage (7;10-20) or directly from the colonic serosa near the
tumor site (10;21-23). However, results varied from about 3% up to over 30% after
peritoneal lavage and from 9% up to 42% in serosa biopsies. Because of these very
diverse findings, the prognostic value of peritoneal tumor cells remained at least
controversial.(18;20;23)

However, since the results of the EVOCAPE 2 study were published in 2013 the use
of cytology from peritoneal lavages to guide different treatment approaches seems
questionable. This prospective multicenter study showed that the presence of free
intraperitoneal cancer cells (IPCC) was not an independent prognostic factor.
Moreover, the presence of IPCC detected by peritoneal cytology didn’t appear to
predict development of PC. (24) Overall, peritoneal seeding of tumor cells remains an
incomprehensible process.

For decades, patients with PC from CRC were considered as not curable and
treatment strategies focused on palliative systemic chemotherapy in combination with
palliative surgery if necessary.(3) In contrast, new systemic chemotherapy
approaches in combination with cytoreductive surgery (CRS) associated with
hyperthermic intraperitoneal chemotherapy (HIPEC), and both procedures are closely
connected, represent an approach to treat peritoneal seeding of CRC more
efficiently.

However, the treatment of PC can and should be approached on an individual basis

with respect to the distinct patient, the tumor biology, and the variety of therapeutic
options available. This article reviews current treatment options, with a focus of
recent and ongoing research, and potential future directions for the treatment of PC
from CRC.

2. Cytoreductive Surgery (CRS)

Prior to hyperthermic intraperitoneal chemotherapy (HIPEC) cytoreductive surgery
(CRS) with resection of all visible tumor lesion is obligatory to pursue the curative aim
of this kind of treatment. (25) Therefore, the amount of PC and the affected visceral
organs determine the surgical intervention in order to receive tumor-free status. That
is the reason why performed procedures usually start with a fully exploration of the
abdomen and can reach from local to total peritonectomy, different visceral
resections (colon, rectum, small bowel, hyster- and ovarectomy, even in exceptional
cases liver and stomach) and infragastral omentectomy. In this context, selection of
patients who benefit from CRS and HIPEC plays a pivotal role in the evaluation of the
appropriate treatment concept. Overall, most centers specify the degree of PC using
the Peritoneal Cancer Index (PCI) classification after laparotomy and exploration of
the whole abdominal cavity (fig.1). (26;27) Since the PCI is based on an
intraoperative estimation of tumor spread, especially the preoperative classification of
patients and therefore the selection of patients with the most benefit of this extended
operation is still challenging. CT scan or MRI show distant metastasis i.e. in the liver
but an exact staging of PC is not possible. Pelz et al. introduced the Peritoneal
Surface Disease Severity Score (PSDSS: 2-22 points) which might help to recognize
appropriate patients.(28) The PSDSS includes a preoperative PCI estimated with a
CT scan, clinical symptoms and histopathology which are scored I-IV. (29)

In contrast, the recently presented prognostic score called colorectal peritoneal score
(COREP) combines histopathology, hemoglobin, white cell count and the
development of 4 tumor markers. It seems that COREP is superior to predict
outcome of patients suffering from CRC associated with PC. (30)

In addition, laparoscopy might be beneficial, especially if the small bowel and its
mesenteric are affected which might make a complete resection infeasible.

Moreover, evidence of extraabdominal metastasis usually represents a

contraindication for CRS whereas limited liver resections in case of hepatic tumor
lesions are no obstacle to pursue curative intention. (31;32) The consensus
statement of the International Peritoneal Surface Malignancy Group considers up to
three small hepatic tumor lesions as threshold for the chance of a complete
cytoreduction. (33)

However, more recently circulating tumor cells (CTCs) isolated from the peripheral
blood have been reported to be good prognostic and predictive markers in patients
with PC resulting from colon cancer. The detection and further characterization of
CTCs could be used as a new tool to identify a subpopulation of patients who would
benefit the most from CRS + HIPEC treatment. (34)

In general, survival benefits need to be considered in the context of significant risks

of surgical complications like anastomosis leakage, intraabdominal abscess, fistula
and ileus. (35) Postoperatively, completeness of cytoreduction (CC) should be
documented to evaluate subsequent therapy (tab. 1). (36) Furthermore, every patient
with PC due to CRC should be included in a multidisciplinary treatment concept.

3. Hyperthermic intraperitoneal chemotherapy (HIPEC)

In the 80s and early 90s of the twentieth century several groups started the
application of chemotherapeutic drugs intraperitoneally for patients with PC
originated from ovarian, colorectal and gastric cancer with initially rather
disappointing results. (37-41) The rationale behind this approach was to apply
chemotherapy directly on-site to the tumor cells using high drug doses. Following this
line, Morgan et al. showed that the median intraperitoneal peak concentration of
gemcitabine is over 1000 fold higher than median peak plasma level.(42)

According to current research, the peritoneum is not just a membrane, it rather

creates a structural and functional complex together with the underlying tissue
including different types of cells and microvessels.(43) Interestingly, the peritoneum
itself does not influence the transport of fluid or small solutes. (44;45) These
conditions have to be considered for the mechanism and the impact of intraperitoneal
chemotherapy. In particular, the tissue penetration of several chemotherapeutic
drugs is important for the oncological effect and depends on the distinct
microanatomy. (46) (47) The maximum penetration depth of only 3- 5 mm is mainly
limited by the vasculature than the cellular uptake.(48)

Taken into account that previously hyperthermia showed an oncological benefit

(49;50), intraperitoneal chemotherapy with heated drugs was initiated. Already 1980
Spratt et al. reported a case of a patient with pseudomyxoma peritonei treated by
intraperitoneal hyperthermic chemotherapy, which was well tolerated and the
procedure was presented as safe and feasible. (51) Subsequently, heated
chemotherapy was also used intraperitoneally in patients with gastric cancer (52) and
several studies analyzed different hyperthermic drug application. (53-55)

In general, cell activity is strongly dependent on temperature and although cellular

thermotolerance induction is initiated at 40°C (56), susceptibility to cell destroying
mechanisms increases in malignant cells. (57-59). Furthermore, several results
indicate that hyperthermia intensifies cytotoxicity of chemotherapeutical drugs.
(58;60;61) These effects are especially shown for doxorubicin, platinum-based
chemotherapy, mitomycin c, irinotecan and gemcitabine.(53;62-64) In addition, it
seems that hyperthermic application into the peritoneal cavity enhances tissue and
tumor penetration of chemotherapeutics.(48;65;66) Regarding oxaliplatin, heat
enhances peritoneal tissue penetration, while systemic absorption is reduced, which
may minimizes systemic toxicity.(67)
When HIPEC, the acronym was first used in dutch publications at the end of the
nineties (68;69), became more popular several questions had to be answered such
as which chemotherapeutic drug in which dose, for how long and at which
temperature should be used. Furthermore, specific devices are required to circulate
the drug through the abdomen and to maintain the correct temperature. Based on the
findings that tumor cells are especially susceptible to cytotoxic effects between 41°C
to 43°C (70) inflow respectively outflow temperature should be within this
range.(71;72)

One of the major problems seems to be the exposure intensity and in particular how
to calculate the peritoneal surface. Usually, drug dose is based on patient’s body
surface area (mg/m2).(70) But during the HIPEC, preferably, the whole peritoneal
cavity should be in contact with the circulating chemotherapeutic drug which can be
achieved by using a certain volume of the carrier solution.(73;74) Mostly between two
and four liters are recommended.(75;76) But also the type of carrier solution is
supposed to influence the cytotoxicity and the efficacy of the chemotherapeutic drug.
Most groups prefer isotonic salt or dextrose solutions though there are experimental
hints for advantages of hypo- just as for hypertonic solutions.(71).

Different chemotherapeutics were considered for the intraperitoneal treatment of

metastatic colorectal cancer. Todays most used drugs and protocols are displayed in
table 2. Astonishingly, looking at different HIPEC protocols there is still a wide range
between 30 min up to 120 min in the duration of intraperitoneal chemotherapy. (72)
Unfortunately, up to now exposure time, dose-response curve and consequently time
to reach the maximum of tumor cell killing (77) cannot be exactly determined.
Therefore each center has to decide for how long the HIPEC is performed.

Using HIPEC the curative strategy can only be pursued after surgical complete
cytoreduction.(78;79) Nevertheless, several studies showed also palliative effects of
HIPEC in case of extensive ascites. (80;81)
Next step was the introduction of bidirectional chemotherapy which means
intraoperative application of intraperitoneal and intravenous drugs.(73). This
therapeutic combination was based on formerly found data of synergistic effect of
oxaliplatin and 5-fluorouracil.(82;83)

4. Hyperthermic intraperitoneal chemotherapy (HIPEC) -

Technique
The hyperthermic intraperitoneal chemotherapy is only one of three techniques for
the intraperitoneal application of chemotherapeutic drugs.

During the early postoperative intraperitoneal chemotherapy (EPIC) the

chemotherapeutic agent is administered through special catheters into the abdominal
cavity on the days after the operation. This procedure can be repeated multiple times
but it does not include hyperthermia.(84;85) However, results from Elias et al.
indicate that HIPEC is significantly more effective to cure PC due to CRC than
EPIC.(86) The third technique is using pressurized intraperitoneal aerosol
chemotherapy (PIPAC) and represents a therapeutic option for patients who are not
eligible for HIPEC. In these patients chemotherapy is applied as aerosol and under
pressure without prior surgical cytoreduction.(87;88) But use of PIPAC is limited due
to the requirement of special devices to produce the aerosol and to create the
pressure before injection.(88)

In contrast, HIPEC starts immediately after the surgical part of the procedure when
the patient is still under anesthesia and in the operation room. Usually it is a one-time
procedure and as already mentioned in section 3, hyperthermia represents an
important and characteristic feature.

Focusing on HIPEC, there are two different techniques to deliver heated

chemotherapy into the peritoneal cavity, the open procedure or “Coliseum” technique
and on the other hand the close technique after closure of the abdominal wall.(89) In
contrast to previous reports (90), there is no recent evidence for significant
differences between both techniques, though randomized trials are still pending.(91)

The open procedure was introduced by Sugarbaker and his group.(92) A plastic
sheet placed over a retractor forms with the open abdomen a cavity similar to a
coliseum, in which the heated chemotherapeutic solution is filled. In this setting the
surgeon can make sure that the whole abdominal space receives sufficient drug
exposure (fig.2). However, there is a significant temperature loss during the
procedure and the open use of chemotherapeutics brings along safety issues for the
medical staff that need to be addressed.(89) The invention of an acrylic cylinder
called the peritoneal cavity expander (PCE) represented a modification of the open
technique (93;94), which make it possible to maintain continuously higher
temperature (95) but it does not decrease the risk of contact to the chemotherapy
agent.(91)

However, the closed technique is probably the most widely used procedure.(91) It
implies the complete closure of the laparotomy after cytoreduction was performed
and special drainages were put in place. Chemotherapeutic agents should circle
through the peritoneal cavity in order to achieve sufficient distribution in all abdominal
areas. Therefore, drainages are required for inflow and for outflow, respectively.
Furthermore, a special pumping device as well as a heat exchanger renders possible
a continuous circulation of hyperthermic chemotherapy, which has to be adjusted
according to intraabdominal temperature probes (fig.3). The main advantage of the
closed procedure is little heat loss in the abdomen and higher safety for the medical
staff due to the minimization of chemotherapeutic exposure.(91) In addition, elevated
intraabdominal pressure can be kept up almost constantly, which lead to an
increased drug uptake.(87;96)

5. Colorectal cancer
Based on findings from several uncontrolled studies showing that aggressive
cytoreduction in combination with hyperthermic intraperitoneal chemotherapy
(HIPEC) is superior to standard treatment in patients with PC of CRC origin, the first
randomized controlled trial was published in 2003 by Verwaal VJ and colleagues.
(97) In this single-institution phase III trial patients (n=105) were randomly assigned
to receive either standard treatment consisting of systemic chemotherapy
(fluorouracil-leucovorin) with or without palliative surgery, or experimental therapy
consisting of aggressive cytoreduction with mitomycin C (MMC) HIPEC, followed by
the same systemic chemotherapy regime. Presence of macroscopic tumor spread
was detected in seven abdominal regions. After a median follow-up of 21.6 months,
the median survival was 12.6 months in the standard therapy arm and 22.3 months in
the experimental therapy arm. A more detailed analysis of the HIPEC group revealed
that after complete tumor resection only one of 18 patients died, but 14 of 21 with
limited and seven of ten with extensive residual disease. In addition, patients with six
to seven regions tumor involved (correlating a higher PCI) had a median survival of
5.4 months, in contrast to those with zero to five regions (median survival >29
months). The patients from this trial were then analyzed a second time after a follow-
up of 6 years.(98) The long-term results show that the median progression-free
survival was 7.7 months in the control arm and 12.6 months in the HIPEC arm (P =
0.020). The median disease-specific survival was 12.6 months in the control arm and
22.2 months in the HIPEC arm (P = 0.028). Furthermore, the study showed a median
survival of 48 months and a 5-year survival of 45% for those patients in the HIPEC
group in whom at least a R1 resection (representing CC 0/1) was achieved. But one
has also to address the limits of this trial, because there was usually no surgery in the
standard group and systemic chemotherapy did not correspond with the currently
used chemotherapeutic drugs. However, these long term survival data after CRS and
HIPEC confirmed a previous retrospective analysis from the same group. Between
1995 and 2003, 117 patients were treated by CRS and HIPEC and the median
survival was 21.8 months. The 1-, 3-, and 5-year survival rates were 75%, 28%, and
19%, respectively.(99) In a larger retrospective multicenter study of 506 patients from
28 institutions operated between May 1987 and December 2002, the international
experience with this combined treatment were evaluated.(100) All patients had CRS
and perioperative intraperitoneal chemotherapy. 5-year survival rate depended on
completeness of cytoreduction (31 months for CC-0, 15 months for CC-1 and no
patient alive after five years with CC-2) as well as the extent of carcinomatosis (33%
for limited and 11% for extended carcinomatosis).

Since in the earlier studies mitomycin C (MMC) was frequently used for
intraperitoneal chemotherapy and fluorouracil-based chemotherapy was administered
without modern chemotherapeutic agents, these studies were repeated and the
outcome compared to systemic chemotherapy containing oxaliplatin or irinotecan. In
a case control study patients (n=48) were retrospectively included who were treated
with palliative systemic chemotherapy containing oxaliplatin or irinotecan (standard
group) and compared with (n=48) patients who had additionally undergone CRS plus
HIPEC and were evaluated prospectively (HIPEC group). Median follow-up was 95.7
months in the standard group versus 63 months in the HIPEC group. Two-year and
5-year overall survival rates were 81% and 51% for the HIPEC group, respectively,
and 65% and 13% for the standard group, respectively. Median survival was 23.9
months in the standard group versus 62.7 months in the HIPEC group.(101)

In a prospective multicenter registry in Belgian a bidirectional approach for the

intraoperative chemotherapy was introduced. At the end of the surgical procedure,
about 1 h before starting the actual HIPEC procedure, systemic folinic acid and 5-
fluorouracil were administered additionally to the HIPEC with oxaliplatin. In this study
48 consecutive patients underwent complete (R0/1) cytoreductive surgery (CCRS)
and HIPEC. At a median follow-up of 22.7 months, overall survival was 97.9% at 1
year and 88.7% at 2 years. Disease free survival at 1 year was 65.8% and 45.5% at
2 years. The median time until recurrence was 19.8 months.(102) Although these
data are promising, there is still no comparison between bidirectional intraoperative
chemotherapy and HIPEC alone.

In order to increase the benefit for the patients and to decrease morbidity of the CRS
and HIPEC treatment several studies tried to improve the patient selection. In a
larger retrospective multicenter study of 506 patients between May 1987 and
December 2002, positive independent prognostic indicators by multivariate analysis
were complete cytoreduction, treatment by a second procedure, limited extent of PC,
age less than 65 years, and use of adjuvant chemotherapy. The use of neoadjuvant
chemotherapy, lymph node involvement, presence of liver metastasis, and poor
histologic differentiation were negative independent prognostic indicators.(100)
These data were confirmed by a Meta-analysis including 50 articles that
demonstrated 1 or more clinicopathological variables on overall survival after CRS
and HIPEC in patients with PC originated from CRC.(103)

In a subgroup analysis of the HIPEC group within the first randomized controlled
phase III trial of 105 patients (n=105) they could furthermore show that the survival
was significantly better if only 0 to 5 of the 7 regions of the abdominal cavity were
affected by PC at the time of surgery and if the cytoreduction was macroscopically
complete (R0/1).(97) In the above mentioned prospective multicenter registry of 48
consecutive patients, who underwent CRS and HIPEC, only the difference between
low and high PC index was found to be a significant factor influencing the overall
survival.(102) In the case of PCI over 17 it seems that survival benefit of CRS and
HIPEC is limited.(104)
Beside the oncological benefit, there are multiple publications anlayzing
complications and quality of life after CRS/HIPEC. A prospective study of patients
with peritoneal carcinomatosis from colorectal cancer using the European
Organization for the Research and Treatment of Cancer Core Quality of Life
Questionnaire (QLQ-C30) and the colorectal module (QLQ-CR29) revealed a
decrease of physical and role functioning scores at 3 months but a return to baseline
at 6 months and an increase from 6 to 12 months. Worse outcome in terms of QoL
resulted from longer duration of surgery, higher PCI, requirement of stoma and earlier
recurrence of disease.(105) These data of a rather small cohort were basically
confirmed by a large study about quality of life after CRS/HIPEC.(106) Major
complications like intraabdominel abscess, bleeding, symptomatic pleural effusion
and anastomotic leakage occur in about 5-10% of all cases, but even then quality of
life seemed to recover after 6 months similar to those patients without
complications.(107)

6. Conclusion
Introduction of CRS and HIPEC represents a significant improvement of the
prognosis of patients suffering from PC originated from CRC. Over the last years,
feasibility, safety and efficacy of the administration of HIPEC has been established.
Furthermore, additional application of i.v. chemotherapy in combination with HIPEC
in a bidirectional setting enhances the oncological outcome. However, selection of
appropriate patients is required to achieve the maximum benefit.

7. Expert commentary
Peritoneal carcinomatosis from colorectal cancer still represents an advanced stage
of malignancy associated with a poor prognosis for the patients. It is not a long time
ago since this condition has been considered as not curable and just palliative
treatment strategies were offered. However, a lot of effort has been made to
understand tumor biology and especially to ameliorate the outcome. Since surgery
alone or systemic chemotherapy did not result in a satisfying response rates, in the
nineties, first attempts were started to bring the peritoneal carcinoma cells into direct
contact with chemotherapeutic agents.In fact, following current treatment approaches
this kind of metastatic spread does not any longer mean a palliative situation per se.
Especially in the case of PC from CRC prospective randomized trials revealed a
significant increase of survival rate after CRS with HIPEC compared to systemic
chemotherapy alone,keeping in mind that, meanwhile, new chemotherapeutics for
systemic chemotherapy have been introduced and randomized controlled trials
comparing them to CRS with HIPEC are still pending. In addition to surgical
interventions and systemic chemotherapy the direct administration of
chemotherapeutics into the abdominal cavity and especially heating of these drugs
before application offered a promising therapeutic option. During this procedure
chemotherapy directly gets in touch with the site of metastasis and heating
additionally increases the cytotoxic effect. Technically, it has to be ensure that the
chemotherapeutical agent reaches every region in the abdomen with an appropriate
concentration and temperature. In this context, the open procedure seems to have an
advantage in distribution but with currently available equipment including
continuously monitored circulation and temperature, the closed procedure is also
offering a stable and complete perfusion. Over the recent years, the respective
chemotherapeutic agent, time and temperature of administration as well as special
devices for HIPEC were optimized and made the procedure feasible, safe for medical
staff and well tolerated with a reasonable risk of complications for the patients.
Initially, mitomycin C has been used but in recent years more and more groups are
using oxaliplatin for the hyperthermic i.p. administration. Supplementary, it has been
shown that a bidirectional chemotherapy, with i.v. application of 5-FU additional to
HIPEC, seems to have a further benefit. Nevertheless, as described in table 2, there
are different drug protocols for HIPEC in PC from CRC and any superiority of one of
them has not yet been proven. This uncertainty still remains a major challenge for the
future.

Dependent on the metastatic extension, complete CRS followed by HIPEC

represents a curative approach. But it has to emphazised, that the currently available
data clearly show that only the complete surgical cytoreduction represents the
requirement to achieve a better prognosis. For this purpose, special techniques and
intraoperative procedures are inevitable and need to be trained. In addition,
preoperative assessment requires a certain quantity of experience to select suitable
patients who has the chance to benefit from this complex therapy. For the reason of
patient selection as well as for the accurate and exact performance of the
intraperitoneal chemotherapy, CRS and HIPEC should only be performed in well-
educated surgical centers. Beside the curable approach, several publications show a
positive palliative effect of HIPEC in case of malignant ascitis. The use of HIPEC in
this context should be thoroughly considered.

For the future, the combination with systemic chemotherapy in a neoadjuvant as well
as in an adjuvant treatment concept has to be discussed. There are several ongoing
clinical trials which will give further detailed information about the benefit of this
combination of oncological therapies. Preliminary data are promising and probably,
the future will bring a standard multimodal treatment concept for patients with PC due
to CRC.

Furthermore, it would be of special interest if prophylactic or second look operations

in patients with major risks for PC have an impact of the outcome.

8. Five-year view
In the next years, there are still several clinical issues that need to be addressed by
the ongoing oncological research. During the last international congress on
peritoneal surface malignancies (PSOGI) 2016 in Washington DC, some remaining
questions and data from recent trials were presented. In particular, analysis of the
recently completed PRODIGE 7 trial is eagerly awaited. This prospective randomized
trial recruited patients with peritoneal carcinomatosis due to colorectal cancer and
compared systemic chemotherapy after surgical cytoreduction with and without
HIPEC. All patients received CRS with additional i.v. 5-fluorouracil and leucovorin for
30 min followed by 6 months of systemic chemotherapy. The only difference between
both groups was a course of 30 min HIPEC with oxaliplatin. The primary endpoint
was overall survival and secondary endpoints were recurrence free survival, toxicity
and surgical morbidity.

Based on promising data from retrospective studies the combination of CRS/HIPEC

with systemic chemotherapy represents a main focus of ongoing trials.(108;109) The
prospective multicenter phase II COMBATAC study investigate CRS with
bidirectional HIPEC in combination with perioperative systemic chemotherapy
including cetuximab.(110) However, systemic chemotherapy with bevacicumab in
patients receiving CRS/HIPEC is the subject of BEV-IP, another prospective phase II
study.(111)

In contrast, the COLOPEC trial about adjuvant HIPEC for primary colon cancer is
addressing the question if HIPEC in an adjuvant setting helps to prevent recurrence
and beyond that increases overall survival.(112)

In this context, Elias et al. could show that selected patients with risk of developing
PC after resection of the primary tumor benefit from a second look surgery.(113) and
several data suggest that CRS/HIPEC in an adjuvant seeting improve overall
survival.(114) The multicentric phase III trial “Comparing Simple Follow-up to
Exploratory Laparotomy Plus "in Principle" (Hyperthermic Intraperitoneal
Chemotherapy) HIPEC in Colorectal Patients (ProphyloCHIP)” will hopefully give us
some answers if HIPEC in combination with the standard adjuvant chemotherapy can
improve the prognosis in patients with high risk of developing peritoneal
carcinomatosis.(115)(116)

However, more urgent are the development of new strategies to prevent peritoneal
carcinomatosis from colorectal cancer.(117) Therefore, in next few years the question
needs to be answered if a prophylactic HIPEC can play a pivotal role in this context.
For this purpose the PROMENADE trial is currently ongoing (ClinicalTrials.gov
identifier NCT02974556).

9. Key issues
 Previously, peritoneal carcinomatosis from colorectal cancer was associated
with poor prognosis.

 In the 1980s first attempts were undertaken to for local chemotherapy in the
peritoneal cavity and revealed good feasibility and satisfying tolerability.

 Two main procedures (open and close abdomen) have been established to
applicate chemotherapeutics intraperitoneal.

 Especially heating of these drugs before application increased the cytotoxic

effect and therefore offered a promising therapeutic option.
 Subsequently, hyperthermic intraperitoneal chemotherapy (HIPEC) has been
implemented in combination with cytoreductive surgery (CRS) as a curative
strategy.

 Different chemotherapeutic drugs were analyzed as HIPEC agent to treat

peritoneal carcinomatosis due to colorectal cancer.

 Bidirectional HIPEC with additional 5-fluorouracil i.v. represents a promising

approach to improve perioperative chemotherapy in patients with PC due to
CRC.

Funding
This paper was not funded.

Declaration of interest
The authors have no 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.
Reference List
Papers of special note have been highlighted as:

* of interest

** of considerable interest

1. Koppe MJ, Boerman OC, Oyen WJ, Bleichrodt RP. Peritoneal carcinomatosis
of colorectal origin: incidence and current treatment strategies. Ann.Surg.
2006;243:212-22.

2. Chu DZ, Lang NP, Thompson C, Osteen PK, Westbrook KC. Peritoneal
carcinomatosis in nongynecologic malignancy. A prospective study of
prognostic factors. Cancer 1989;63:364-7.

3. Sadeghi B, Arvieux C, Glehen O et al. Peritoneal carcinomatosis from non-

gynecologic malignancies: results of the EVOCAPE 1 multicentric prospective
study. Cancer 2000;88:358-63.

4. Jayne DG, Fook S, Loi C, Seow-Choen F. Peritoneal carcinomatosis from

colorectal cancer. Br.J.Surg. 2002;89:1545-50.

5. Sugarbaker PH, Cunliffe WJ, Belliveau J et al. Rationale for integrating early
postoperative intraperitoneal chemotherapy into the surgical treatment of
gastrointestinal cancer. Semin.Oncol. 1989;16:83-97.

6. Sugarbaker PH. Observations concerning cancer spread within the peritoneal

cavity and concepts supporting an ordered pathophysiology. Cancer
Treat.Res. 1996;82:79-100.

7. Yang SH, Lin JK, Lai CR et al. Risk factors for peritoneal dissemination of
colorectal cancer. J.Surg.Oncol. 2004;87:167-73.

8. Homma Y, Hamano T, Akazawa Y et al. Positive peritoneal washing cytology

is a potential risk factor for the recurrence of curatively resected colorectal
cancer. Surg.Today 2014;44:1084-9.

9. Honore C, Goere D, Souadka A, Dumont F, Elias D. Definition of patients

presenting a high risk of developing peritoneal carcinomatosis after curative
surgery for colorectal cancer: a systematic review. Ann.Surg.Oncol.
2013;20:183-92.

10. Uras C, Altinkaya E, Yardimci H et al. Peritoneal cytology in the determination

of free tumour cells within the abdomen in colon cancer. Surg.Oncol.
1996;5:259-63.

11. Horattas MC, Evasovich MR, Topham N. Colorectal carcinoma and the
relationship of peritoneal cytology. Am.J.Surg. 1997;174:334-7.
12. Kim SH, Milsom JW, Gramlich TL et al. Does laparoscopic vs. conventional
surgery increase exfoliated cancer cells in the peritoneal cavity during
resection of colorectal cancer? Dis.Colon Rectum 1998;41:971-8.

13. Wind P, Norklinger B, Roger V, Kahlil A, Guin E, Parc R. Long-term prognostic

value of positive peritoneal washing in colon cancer. Scand.J.Gastroenterol.
1999;34:606-10.

14. Guller U, Zajac P, Schnider A et al. Disseminated single tumor cells as

detected by real-time quantitative polymerase chain reaction represent a
prognostic factor in patients undergoing surgery for colorectal cancer.
Ann.Surg. 2002;236:768-75.

15. Bosch B, Guller U, Schnider A et al. Perioperative detection of disseminated

tumour cells is an independent prognostic factor in patients with colorectal
cancer. Br.J.Surg. 2003;90:882-8.

16. Kanellos I, Demetriades H, Zintzaras E, Mandrali A, Mantzoros I, Betsis D.

Incidence and prognostic value of positive peritoneal cytology in colorectal
cancer. Dis.Colon Rectum 2003;46:535-9.

17. Yamamoto S, Akasu T, Fujita S, Moriya Y. Long-term prognostic value of

conventional peritoneal cytology after curative resection for colorectal
carcinoma. Jpn.J.Clin.Oncol. 2003;33:33-7.

18. Nishikawa T, Watanabe T, Sunami E, Tsuno NH, Kitayama J, Nagawa H.

Prognostic value of peritoneal cytology and the combination of peritoneal
cytology and peritoneal dissemination in colorectal cancer. Dis.Colon Rectum
2009;52:2016-21.

19. Noura S, Ohue M, Seki Y, Yano M, Ishikawa O, Kameyama M. Long-term

prognostic value of conventional peritoneal lavage cytology in patients
undergoing curative colorectal cancer resection. Dis.Colon Rectum
2009;52:1312-20.

20. Nakamura K, Iinuma H, Aoyagi Y, Shibuya H, Watanabe T. Predictive value of

cancer stem-like cells and cancer-associated genetic markers for peritoneal
recurrence of colorectal cancer in patients after curative surgery. Oncology
2010;78:309-15.

21. Zeng Z, Cohen AM, Hajdu S, Sternberg SS, Sigurdson ER, Enker W. Serosal
cytologic study to determine free mesothelial penetration of intraperitoneal
colon cancer. Cancer 1992;70:737-40.

22. Ojima H, Sasaki S, Fujisawa T et al. Utility of serosal stamp cytology as an

indicator for high-risk peritoneal metastasis in colorectal cancer surgery.
Hepatogastroenterology 2003;50:87-90.

23. Baskaranathan S, Philips J, McCredden P, Solomon MJ. Free colorectal

cancer cells on the peritoneal surface: correlation with pathologic variables
and survival. Dis.Colon Rectum 2004;47:2076-9.
24. Cotte E, Peyrat P, Piaton E et al. Lack of prognostic significance of
conventional peritoneal cytology in colorectal and gastric cancers: results of
EVOCAPE 2 multicentre prospective study. Eur.J.Surg.Oncol. 2013;39:707-
14.

25. Sugarbaker PH. Peritonectomy procedures. Surg.Oncol.Clin.N.Am.

2003;12:703-27, xiii.

26. *Glehen O, Gilly FN. Quantitative prognostic indicators of peritoneal surface

malignancy: carcinomatosis, sarcomatosis, and peritoneal mesothelioma.
Surg.Oncol.Clin.N.Am. 2003;12:649-71. Introduction of the Peritoneal
Cancer Index (PCI) which is currently a very common used evaluation of
PC.

27. Sugarbaker PH. Management of peritoneal-surface malignancy: the surgeon's

role. Langenbecks Arch.Surg. 1999;384:576-87.

28. Chua TC, Morris DL, Esquivel J. Impact of the peritoneal surface disease
severity score on survival in patients with colorectal cancer peritoneal
carcinomatosis undergoing complete cytoreduction and hyperthermic
intraperitoneal chemotherapy. Ann.Surg.Oncol. 2010;17:1330-6.

29. Pelz JO, Stojadinovic A, Nissan A, Hohenberger W, Esquivel J. Evaluation of

a peritoneal surface disease severity score in patients with colon cancer with
peritoneal carcinomatosis. J.Surg.Oncol. 2009;99:9-15.

30. Cashin PH, Graf W, Nygren P, Mahteme H. Comparison of prognostic scores

for patients with colorectal cancer peritoneal metastases treated with
cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
Ann.Surg.Oncol. 2013;20:4183-9.

31. Kianmanesh R, Scaringi S, Sabate JM et al. Iterative cytoreductive surgery

associated with hyperthermic intraperitoneal chemotherapy for treatment of
peritoneal carcinomatosis of colorectal origin with or without liver metastases.
Ann.Surg. 2007;245:597-603.

32. Chua TC, Yan TD, Zhao J, Morris DL. Peritoneal carcinomatosis and liver
metastases from colorectal cancer treated with cytoreductive surgery
perioperative intraperitoneal chemotherapy and liver resection.
Eur.J.Surg.Oncol. 2009;35:1299-305.

33. Esquivel J, Sticca R, Sugarbaker P et al. Cytoreductive surgery and

hyperthermic intraperitoneal chemotherapy in the management of peritoneal
surface malignancies of colonic origin: a consensus statement. Society of
Surgical Oncology. Ann.Surg.Oncol. 2007;14:128-33.

34. Melero JT, Ortega FG, Gonzalez AM et al. Prognostic factor analysis of
circulating tumor cells in peripheral blood of patients with peritoneal
carcinomatosis of colon cancer origin treated with cytoreductive surgery plus
an intraoperative hyperthermic intraperitoneal chemotherapy procedure (CRS
+ HIPEC). Surgery 2016;159:728-35.
35. Chua TC, Yan TD, Saxena A, Morris DL. Should the treatment of peritoneal
carcinomatosis by cytoreductive surgery and hyperthermic intraperitoneal
chemotherapy still be regarded as a highly morbid procedure?: a systematic
review of morbidity and mortality. Ann.Surg. 2009;249:900-7.

36. Jacquet P, Sugarbaker PH. Clinical research methodologies in diagnosis and

staging of patients with peritoneal carcinomatosis. Cancer Treat.Res.
1996;82:359-74.

37. Speyer JL, Myers CE. The use of peritoneal dialysis for delivery of
chemotherapy to intraperitoneal malignancies. Recent Results Cancer Res.
1980;74:264-9.

38. Ozols RF, Young RC, Speyer JL et al. Phase I and pharmacological studies of
adriamycin administered intraperitoneally to patients with ovarian cancer.
Cancer Res. 1982;42:4265-9.

39. Sugarbaker PH, Gianola FJ, Barofsky I, Hancock SL, Wesley R. 5-Fluorouracil
chemotherapy and pelvic radiation in the treatment of large bowel cancer.
Decreased toxicity in combined treatment with 5-fluorouracil administration
through the intraperitoneal route. Cancer 1986;58:826-31.

40. Sugarbaker PH, Graves T, DeBruijn EA et al. Early postoperative

intraperitoneal chemotherapy as an adjuvant therapy to surgery for peritoneal
carcinomatosis from gastrointestinal cancer: pharmacological studies. Cancer
Res. 1990;50:5790-4.

41. Yu WS, Sugarbaker PH. Early postoperative intraperitoneal chemotherapy for

gastric cancer. Cancer Treat.Res. 1991;55:265-75.

42. Morgan RJ, Jr., Synold TW, Xi B et al. Phase I trial of intraperitoneal
gemcitabine in the treatment of advanced malignancies primarily confined to
the peritoneal cavity. Clin.Cancer Res. 2007;13:1232-7.

43. Flessner MF. The transport barrier in intraperitoneal therapy. Am.J.Physiol

Renal Physiol 2005;288:F433-F442.

44. Flessner M, Henegar J, Bigler S, Genous L. Is the peritoneum a significant

transport barrier in peritoneal dialysis? Perit.Dial.Int. 2003;23:542-9.

45. de LV, V, Stuart OA, Mohamed F, Sugarbaker PH. Extent of parietal

peritonectomy does not change intraperitoneal chemotherapy
pharmacokinetics. Cancer Chemother.Pharmacol. 2003;52:108-12.

46. Ozols RF, Locker GY, Doroshow JH, Grotzinger KR, Myers CE, Young RC.
Pharmacokinetics of adriamycin and tissue penetration in murine ovarian
cancer. Cancer Res. 1979;39:3209-14.

47. Los G, Verdegaal EM, Mutsaers PH, McVie JG. Penetration of carboplatin and
cisplatin into rat peritoneal tumor nodules after intraperitoneal chemotherapy.
Cancer Chemother.Pharmacol. 1991;28:159-65.
48. El-Kareh AW, Secomb TW. A theoretical model for intraperitoneal delivery of
cisplatin and the effect of hyperthermia on drug penetration distance.
Neoplasia. 2004;6:117-27.

49. Cavaliere R, Ciocatto EC, Giovanella BC et al. Selective heat sensitivity of

cancer cells. Biochemical and clinical studies. Cancer 1967;20:1351-81.

50. Overgaard J. Effect of hyperthermia on malignant cells in vivo. A review and a

hypothesis. Cancer 1977;39:2637-46.

51. Spratt JS, Adcock RA, Muskovin M, Sherrill W, McKeown J. Clinical delivery
system for intraperitoneal hyperthermic chemotherapy. Cancer Res.
1980;40:256-60.

52. Koga S, Shimizu N, Maeta M, Hamazoe R, Izumi A. [Application of heat

combined with antineoplastic agent administration in the treatment of cancer
(with special reference to malignancy of the digestive system)]. Gan To
Kagaku Ryoho 1983;10:358-65.

53. Barlogie B, Corry PM, Drewinko B. In vitro thermochemotherapy of human

colon cancer cells with cis-dichlorodiammineplatinum(II) and mitomycin C.
Cancer Res. 1980;40:1165-8.

54. Wallner KE, Li GC. Effect of drug exposure duration and sequencing on
hyperthermic potentiation of mitomycin-C and cisplatin. Cancer Res.
1987;47:493-5.

55. Fernandez-Trigo V, Stuart OA, Stephens AD, Hoover LD, Sugarbaker PH.
Surgically directed chemotherapy: heated intraperitoneal lavage with
mitomycin C. Cancer Treat.Res. 1996;81:51-61.

56. Lepock JR. How do cells respond to their thermal environment?

Int.J.Hyperthermia 2005;21:681-7.

57. Dahl O, Dalene R, Schem BC, Mella O. Status of clinical hyperthermia. Acta
Oncol. 1999;38:863-73.

58. Sticca RP, Dach BW. Rationale for hyperthermia with intraoperative
intraperitoneal chemotherapy agents. Surg.Oncol.Clin.N.Am. 2003;12:689-
701.

59. Sugarbaker PH. Laboratory and clinical basis for hyperthermia as a

component of intracavitary chemotherapy. Int.J.Hyperthermia 2007;23:431-42.

60. Dudar TE, Jain RK. Differential response of normal and tumor microcirculation
to hyperthermia. Cancer Res. 1984;44:605-12.

61. Kampinga HH. Cell biological effects of hyperthermia alone or combined with
radiation or drugs: a short introduction to newcomers in the field.
Int.J.Hyperthermia 2006;22:191-6.
62. Hahn GM, Braun J, Har-Kedar I. Thermochemotherapy: synergism between
hyperthermia (42-43 degrees) and adriamycin (of bleomycin) in mammalian
cell inactivation. Proc.Natl.Acad.Sci.U.S.A 1975;72:937-40.

63. Kusumoto T, Holden SA, Ara G, Teicher BA. Hyperthermia and platinum
complexes: time between treatments and synergy in vitro and in vivo.
Int.J.Hyperthermia 1995;11:575-86.

64. Mohamed F, Marchettini P, Stuart OA, Urano M, Sugarbaker PH. Thermal

enhancement of new chemotherapeutic agents at moderate hyperthermia.
Ann.Surg.Oncol. 2003;10:463-8.

65. Fujimoto S, Takahashi M, Kobayashi K et al. Cytohistologic assessment of

antitumor effects of intraperitoneal hyperthermic perfusion with mitomycin C
for patients with gastric cancer with peritoneal metastasis. Cancer
1992;70:2754-60.

66. Jacquet P, Averbach A, Stuart OA, Chang D, Sugarbaker PH. Hyperthermic

intraperitoneal doxorubicin: pharmacokinetics, metabolism, and tissue
distribution in a rat model. Cancer Chemother.Pharmacol. 1998;41:147-54.

67. Piche N, Leblond FA, Sideris L et al. Rationale for heating oxaliplatin for the
intraperitoneal treatment of peritoneal carcinomatosis: a study of the effect of
heat on intraperitoneal oxaliplatin using a murine model. Ann.Surg.
2011;254:138-44.

68. van ME. [Rhone-Poulenc-Rorer fellowship travel report 1996. A report of a

study trip in relation to the HIPEC-procedure, a current treatment for
abdominal carcinomas]. Oncologica. 1997;14:10-5.

69. Zoetmulder FA, van d, V, Witkamp AJ, Kaag MM, Boot H, Beijnen JH.
[Hyperthermic intra-peritoneal chemotherapy (HIPEC) in patients with
peritoneal pseudomyxoma or peritoneal metastases of colorectal carcinoma;
good preliminary results from the Netherlands Cancer Institute].
Ned.Tijdschr.Geneeskd. 1999;143:1863-8.

70. *Gonzalez-Moreno S, Gonzalez-Bayon LA, Ortega-Perez G. Hyperthermic

intraperitoneal chemotherapy: Rationale and technique. World
J.Gastrointest.Oncol. 2010;2:68-75. Delivers basic information about
background and technique of HIPEC.

71. Kusamura S, Dominique E, Baratti D, Younan R, Deraco M. Drugs, carrier

solutions and temperature in hyperthermic intraperitoneal chemotherapy.
J.Surg.Oncol. 2008;98:247-52.

72. Turaga K, Levine E, Barone 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;21:1501-5.

73. Elias DM, Sideris L. Pharmacokinetics of heated intraoperative intraperitoneal

oxaliplatin after complete resection of peritoneal carcinomatosis.
Surg.Oncol.Clin.N.Am. 2003;12:755-69, xiv.
74. Sugarbaker PH, Stuart OA, Carmignani CP. Pharmacokinetic changes
induced by the volume of chemotherapy solution in patients treated with
hyperthermic intraperitoneal mitomycin C. Cancer Chemother.Pharmacol.
2006;57:703-8.

75. Elias D, Bonnay M, Puizillou JM et al. Heated intra-operative intraperitoneal

oxaliplatin after complete resection of peritoneal carcinomatosis:
pharmacokinetics and tissue distribution. Ann.Oncol. 2002;13:267-72.

76. Sugarbaker PH, Mora JT, Carmignani P, Stuart OA, Yoo D. Update on
chemotherapeutic agents utilized for perioperative intraperitoneal
chemotherapy. Oncologist. 2005;10:112-22.

77. Gardner SN. A mechanistic, predictive model of dose-response curves for cell
cycle phase-specific and -nonspecific drugs. Cancer Res. 2000;60:1417-25.

78. *Glehen O, Mohamed F, Sugarbaker PH. Incomplete cytoreduction in 174

patients with peritoneal carcinomatosis from appendiceal malignancy.
Ann.Surg. 2004;240:278-85. This article describes the necessity of
complete cytoreduction prior to HIPEC to receive oncological benefit.

79. Losa F, Barrios P, Salazar R et al. Cytoreductive surgery and intraperitoneal

chemotherapy for treatment of peritoneal carcinomatosis from colorectal
origin. Clin.Transl.Oncol. 2014;16:128-40.

80. Sangisetty SL, Miner TJ. Malignant ascites: A review of prognostic factors,
pathophysiology and therapeutic measures. World J.Gastrointest.Surg.
2012;4:87-95.

81. Randle RW, Swett KR, Swords DS et al. Efficacy of cytoreductive surgery with
hyperthermic intraperitoneal chemotherapy in the management of malignant
ascites. Ann.Surg.Oncol. 2014;21:1474-9.

82. Mathe G, Kidani Y, Segiguchi M et al. Oxalato-platinum or 1-OHP, a third-

generation platinum complex: an experimental and clinical appraisal and
preliminary comparison with cis-platinum and carboplatinum.
Biomed.Pharmacother. 1989;43:237-50.

83. de GA, Tournigand C, Louvet C et al. [Oxaliplatin, folinic acid and 5-

fluorouracil (folfox) in pretreated patients with metastatic advanced cancer.
The GERCOD]. Rev.Med.Interne 1997;18:769-75.

84. Esquivel J, Vidal-Jove J, Steves MA, Sugarbaker PH. Morbidity and mortality
of cytoreductive surgery and intraperitoneal chemotherapy. Surgery
1993;113:631-6.

85. Jacquet P, Averbach A, Stephens AD, Stuart OA, Chang D, Sugarbaker PH.
Heated intraoperative intraperitoneal mitomycin C and early postoperative
intraperitoneal 5-fluorouracil: pharmacokinetic studies. Oncology 1998;55:130-
8.

86. Elias D, Benizri E, Di PD, Menegon P, Malka D, Raynard B. Comparison of

two kinds of intraperitoneal chemotherapy following complete cytoreductive
 surgery of colorectal peritoneal carcinomatosis. Ann.Surg.Oncol. 2007;14:509-
14.

87. Esquis P, Consolo D, Magnin G et al. High intra-abdominal pressure enhances

the penetration and antitumor effect of intraperitoneal cisplatin on experimental
peritoneal carcinomatosis. Ann.Surg. 2006;244:106-12.

88. Robella M, Vaira M, De SM. Safety and feasibility of pressurized

intraperitoneal aerosol chemotherapy (PIPAC) associated with systemic
chemotherapy: an innovative approach to treat peritoneal carcinomatosis.
World J.Surg.Oncol. 2016;14:128.

89. Neuwirth MG, Alexander HR, Karakousis GC. Then and now: cytoreductive
surgery with hyperthermic intraperitoneal chemotherapy (HIPEC), a historical
perspective. J.Gastrointest.Oncol. 2016;7:18-28.

90. Elias D, Antoun S, Goharin A, Otmany AE, Puizillout JM, Lasser P. Research
on the best chemohyperthermia technique of treatment of peritoneal
carcinomatosis after complete resection. Int.J.Surg.Investig. 2000;1:431-9.

91. *Glehen O, Cotte E, Kusamura S et al. Hyperthermic intraperitoneal

chemotherapy: nomenclature and modalities of perfusion. J.Surg.Oncol.
2008;98:242-6. Presentation and explanation of different HIPEC
procedures.

92. *Stephens AD, Alderman R, Chang D et al. Morbidity and mortality analysis of
200 treatments with cytoreductive surgery and hyperthermic intraoperative
intraperitoneal chemotherapy using the coliseum technique. Ann.Surg.Oncol.
1999;6:790-6. Introduction of the HIPEC procedure

93. Fujimura T, Yonemura Y, Fujita H et al. Chemohyperthermic peritoneal

perfusion for peritoneal dissemination in various intra-abdominal malignancies.
Int.Surg. 1999;84:60-6.

94. Hirose K, Katayama K, Iida A et al. Efficacy of continuous hyperthermic

peritoneal perfusion for the prophylaxis and treatment of peritoneal metastasis
of advanced gastric cancer: evaluation by multivariate regression analysis.
Oncology 1999;57:106-14.

95. Sugarbaker PH. An instrument to provide containment of intraoperative

intraperitoneal chemotherapy with optimized distribution. J.Surg.Oncol.
2005;92:142-6.

96. Jacquet P, Stuart OA, Chang D, Sugarbaker PH. Effects of intra-abdominal

pressure on pharmacokinetics and tissue distribution of doxorubicin after
intraperitoneal administration. Anticancer Drugs 1996;7:596-603.

97. *Verwaal VJ, van RS, de BE et al. 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;21:3737-43. First Randomized trial which show
a benefit of CRS/HIPEC in contrast to systemic chemotherapy alone in
patients with CRC.
 98. *Verwaal VJ, Bruin S, Boot H, van SG, van TH. 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;15:2426-32.
Longtime follow-up of the randomized trial.

99. Verwaal VJ, van RS, Witkamp A, Boot H, van SG, Zoetmulder FA. Long-term
survival of peritoneal carcinomatosis of colorectal origin. Ann.Surg.Oncol.
2005;12:65-71.

100. *Glehen O, Kwiatkowski F, Sugarbaker PH et al. Cytoreductive surgery

combined with perioperative intraperitoneal chemotherapy for the
management of peritoneal carcinomatosis from colorectal cancer: a multi-
institutional study. J.Clin.Oncol. 2004;22:3284-92. Large study which
confirms data from the trial above but also shows that completeness of
cytoreduction is crucial for higher survival rate.

101. Elias D, Lefevre JH, Chevalier J et al. Complete cytoreductive surgery plus
intraperitoneal chemohyperthermia with oxaliplatin for peritoneal
carcinomatosis of colorectal origin. J.Clin.Oncol. 2009;27:681-5.

102. *Hompes D, D'Hoore A, Van CE et al. The treatment of peritoneal

carcinomatosis of colorectal cancer with complete cytoreductive surgery and
hyperthermic intraperitoneal peroperative chemotherapy (HIPEC) with
oxaliplatin: a Belgian multicentre prospective phase II clinical study.
Ann.Surg.Oncol. 2012;19:2186-94. Study introduces CRS including
bidirectional HIPEC with a promising survival rate.

103. Kwakman R, Schrama AM, van Olmen JP et al. Clinicopathological

Parameters in Patient Selection for Cytoreductive Surgery and Hyperthermic
Intraperitoneal Chemotherapy for Colorectal Cancer Metastases: A Meta-
analysis. Ann.Surg. 2016;263:1102-11.

104. Goere D, Souadka A, Faron M et al. Extent of colorectal peritoneal

carcinomatosis: attempt to define a threshold above which HIPEC does not
offer survival benefit: a comparative study. Ann.Surg.Oncol. 2015;22:2958-64.

105. Chia CS, Tan GH, Lim C, Soo KC, Teo MC. Prospective Quality of Life Study
for Colorectal Cancer Patients with Peritoneal Carcinomatosis Undergoing
Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.
Ann.Surg.Oncol. 2016;23:2905-13.

106. Dodson RM, McQuellon RP, Mogal HD et al. Quality-of-Life Evaluation After
Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy.
Ann.Surg.Oncol. 2016;23:772-83.

107. Hamilton TD, Taylor EL, Cannell AJ, McCart JA, Govindarajan A. Impact of
Major Complications on Patients' Quality of Life After Cytoreductive Surgery
and Hyperthermic Intraperitoneal Chemotherapy. Ann.Surg.Oncol.
2016;23:2946-52.
108. Kuijpers AM, Mehta AM, Boot H et al. Perioperative systemic chemotherapy in
peritoneal carcinomatosis of lymph node positive colorectal cancer treated
with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
Ann.Oncol. 2014;25:864-9.

109. Devilee RA, Simkens GA, van Oudheusden TR et al. Increased Survival of
Patients with Synchronous Colorectal Peritoneal Metastases Receiving
Preoperative Chemotherapy Before Cytoreductive Surgery and Hyperthermic
Intraperitoneal Chemotherapy. Ann.Surg.Oncol. 2016;23:2841-8.

110. Glockzin G, Rochon J, Arnold D et al. A prospective multicenter phase II study

evaluating multimodality treatment of patients with peritoneal carcinomatosis
arising from appendiceal and colorectal cancer: the COMBATAC trial.
BMC.Cancer 2013;13:67.

111. Willaert W, Van Der Speeten K, Liberale G, Ceelen W. BEV-IP: Perioperative

chemotherapy with bevacizumab in patients undergoing cytoreduction and
intraperitoneal chemoperfusion for colorectal carcinomatosis. BMC.Cancer
2015;15:980.

112. Klaver CE, Musters GD, Bemelman WA et al. Adjuvant hyperthermic

intraperitoneal chemotherapy (HIPEC) in patients with colon cancer at high
risk of peritoneal carcinomatosis; the COLOPEC randomized multicentre trial.
BMC.Cancer 2015;15:428.

113. Elias D, Honore C, Dumont F et al. Results of systematic second-look surgery

plus HIPEC in asymptomatic patients presenting a high risk of developing
colorectal peritoneal carcinomatosis. Ann.Surg. 2011;254:289-93.

114. Baratti D, Kusamura S, Iusco D et al. Hyperthermic Intraperitoneal

Chemotherapy (HIPEC) at the Time of Primary Curative Surgery in Patients
with Colorectal Cancer at High Risk for Metachronous Peritoneal Metastases.
Ann.Surg.Oncol. 2017;24:167-75.

115. Pinto A, Eveno C, Pocard M. Update on clinical trials in colorectal cancer

peritoneal metastasis. Int.J.Hyperthermia 2017;1-16.

116. ClinicalTrials.gov Identifier:NCT01226394. 2017.

117. Gelli M, Hugueinin JF, Cerebelli C et al. Strategies to prevent peritoneal

carcinomatosis arising from colorectal cancer. Future.Oncol. 2017.

118. Casado-Adam A, Alderman R, Stuart OA, Chang D, Sugarbaker PH.

Gastrointestinal complications in 147 consecutive patients with peritoneal
surface malignancy treated by cytoreductive surgery and perioperative
intraperitoneal chemotherapy. Int.J.Surg.Oncol. 2011;2011:468698.

119. Quenet F, Goere D, Mehta SS et al. Results of two bi-institutional prospective

studies using intraperitoneal oxaliplatin with or without irinotecan during
HIPEC after cytoreductive surgery for colorectal carcinomatosis. Ann.Surg.
2011;254:294-301.
120. Piso P, Glockzin G, von BP et al. Patient selection for a curative approach to
carcinomatosis. Cancer J. 2009;15:236-42.

Figure and table legends:

Figure 1: Peritoneal Cancer Index (PCI): Size and regions of peritoneal lesions to
quantify tumor volume (27;120)
Figure 2: Schematic representation of the open hyperthermic intraperitoneal
chemotherapy(HIPEC) procedure.(92) The heated chemothearpeutic solution
is filled into the colliseum and the whole abdomen is exposed to the drug.
Figure 3: Closed hyperthermic intraperitoneal chemotherapy (HIPEC) procedure with
specific in- and outflow drainages as well as temperature detection.(91)
Table 1: Recommended use of hyperthermic intraperitoneal chemotherapy (HIPEC)
related to the amount of tumor left after surgical procedure described with the
Completeness of Cytoreduction (CC) Score.(36)

End of No visible tumor Up to 2.5mm Between 2.5mm >2.5cm

Operation and 2.5cm

Score CC-0 CC-1 CC-2 CC-3

Cytoreduction complete incomplete

HIPEC  Curative Intent () Optional Symptoms Control

Table 2: This table shows different hyperthermic intraperitoneal chemotherapy
(HIPEC) protocols for peritoneal carcinomatosis due to colorectal cancer,
which are used in special surgical centers. (101) (118) (72) (79) (119)

Cytostatic Drug Dosage Duration Procedure

Oxaliplatin i.p. 300 mg/m2

5-Fluorouracil i.v. 400 mg/m2 30 min closed
Leucovorin i.v. 20 mg/m2

Mitomycin C i.p. 15 mg/m2

Doxorubicin i.p. 15 mg/m2 90 min open
5-Fluorouracil i.v. 400 mg/m2
Leucovorin i.v. 20 mg/m2

Mitomycin C i.p. 40 mg 90 min closed

Mitomycin C i.p. 15 mg/m2

60 min closed
Doxorubicin i.p. 15 mg/m2

Oxaliplatin i.p. 460 mg/m2 30 min open

Oxaliplatin i.p. 460 mg/m2

5-Fluorouracil i.v. 400 mg/m2 30 min open
Leucovorin i.v. 20 mg/m2
Oxaliplatin i.p. 300 mg/m2
30 min closed
Irinotecan i.p. 200 mg/m2