Adjuvant Hyperthermic Intraperitoneal Chemotherapy in Patients With Colon Cancer at High Risk of Peritoneal Carcinomatosis
Phase: PHASE3
Conditions: Colorectal Neoplasms, Peritoneal Neoplasms
Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

 
 
COLOPEC study protocol version 9.3 5-12-2016  
STUDY PROTOCOL 
 
 
 
 
 
 
 
 
 
 
 
 
Adjuvant hyperthermic intraperitoneal chemotherapy in 
patients with colon cancer at high risk of peritoneal 
carcinomatosis; the COLOPEC randomized multicentre 
trial. 
Principal investigators 
P.J. Tanis1, C.J.A. Punt2, V. Verwaal3, M.G.W. Dijkgraaf4, W.A. Bemelman1  
1 
Department of Surgery, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands  
2 
Department of Medical Oncology, Academic Medical Centre, University of Amsterdam 
3 
 Department of Surgery, Catharina hospital, Eindhoven, the NetherlandsClinical Research Unit, Academic 
Medical Centre, University of Amsterdam, Amsterdam, the Netherlands 
 
PhD-students 
C.E.L. Klaver1, G.D. Musters1 
1 
Department of surgery, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands  
 
Participating members / Writing committee: 
R.J. van Ginkel1, B. van Ramshorst2, I.H.J.T. de Hingh3, S.A. Radema4,J.H.W. de Wilt5, E.A. te 
Velde6, J.W.A. Burger7, A. Aalbers8, W.M.U. van Grevenstein9, C.J. Buskens10, J.D.W. van der Bilt10, 
L.A. ten Berg-Lammers11, P. Evers12, J. Pon13, W.J.H.J. Meijerink6, J. Tuynman6, P.H.J. Hemmer1, B. 
van Leeuwen1, A. Bremers5, S. Nienhuijs3, M.J. Wiezer2, D. Boerma2 , P. Snaebjornsson14 
1. 
Department of Surgery, University Medical Centre Groningen, Groningen, the Netherlands 
2. 
Department of Surgery, Antonius hospital, Nieuwegein, the Netherlands  
3. 
Department of Surgery, Catharina hospital, Eindhoven, the Netherlands 
4. 
Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, the Netherlands 
5. 
Department of surgery, Radboud University Medical Centre, Nijmegen, the Netherlands 
6. 
Department of Surgery, VU Medical Centre, Amsterdam, the Netherlands 
7. 
Department of Surgery, Erasmus Medical Centre / Daniel den Hoed, Rotterdam, the Netherlands 
8. 
Department of Surgery, Antoni van Leeuwenhoek hospital / the Netherlands Cancer Institute, Amsterdam, 
the Netherlands 
9. 
Department of Surgery, University Medical Centre Utrecht, Utrecht, the Netherlands 
10. Department of Surgery, Academic Medical Centre, Amsterdam, the Netherlands 
11. Department of Pharmacy, Academic Medical Centre, Amsterdam, the Netherlands 
12. Dutch Cancer Patient Organization ‘Leven met Kanker’ 
13. Society of patients with cancer of the gastrointestinal tract (SPKS), Darmkanker Nederland 

 
 
COLOPEC study protocol version 9.3 5-12-2016  
14. Department of Pathology, Antoni van Leeuwenhoek hospital / the Netherlands Cancer Institute, Amsterdam, 
the Netherlands 
 
 
Academic Medical Centre, Amsterdam, the Netherlands 
 
Trial register: Clinicaltrial.gov 
EudraCT number:  2014-002794-11 
 
Approval Medical Ethical Committee: 
Protocol version 9. 11-11-2016 
 
 
 
 

 
 
COLOPEC study protocol version 9.3 5-12-2016  
Protocol Title 
Adjuvant hyperthermic intraperitoneal chemotherapy in patients with colon cancer at high risk of 
peritoneal carcinomatosis. The COLOPEC randomized multicentre trial. 
 
Protocol ID 
NL49960.018.14 
Short title 
Adjuvant HIPEC in high risk CRC 
Version 
9 
Date 
11-11-2016 
Coordinating investigator/project 
leader 
 
Pieter J. Tanis, MD PhD, surgeon 
Department of Surgery, Academic Medical Center, 
Meibergdreef 9, 1105 AZ Amsterdam, the 
Netherlands 
Phone: +31-20-5669111 
e-mail: p.j.tanis@amc.uva.nl 
 
Principal investigator(s):  
Principle investigators: 
 
Pieter J. Tanis, MD PhD, surgeon 
Department of Surgery, Academic Medical Centre, 
Meibergdreef 9, 1105 AZ Amsterdam, the 
Netherlands 
Phone: +31-20-5669111 
e-mail: p.j.tanis@amc.uva.nl 
 
Kees Punt, MD PhD, Professor of Medical 
Oncology 
Department of Medical Oncology, Academic 
Medical Centre, Meibergdreef 9, 1105 AZ 
Amsterdam, the Netherlands 
Phone: +31-20-5669111 
e-mail: c.punt@amc.uva.nl 
 
Victor Verwaal, MD PhD, surgeon 
Currently not affiliated with an institute 
 
Marcel G.W. Dijkgraaf, PhD, consultant in 
research methodology and statistics 
Clinical Research Unit, Academic Medical Centre, 
Meibergdreef 9, 1105 AZ Amsterdam, the 
Netherlands 
Phone: +31-20-5669111 
e-mail: m.g.dijkgraaf@amc.uva.nl 

 
 
COLOPEC study protocol version 9.3 5-12-2016  
 
Willem A. Bemelman, MD PhD, surgeon, 
Professor of Minimally Invasive Surgery 
Department of Surgery, Academic Medical Centre, 
Meibergdreef 9, 1105 AZ Amsterdam, the 
Netherlands 
Phone: +31-20-5669111 
e-mail: w.a.bemelman@amc.uva.nl 
 
Independent physician(s) 
O.R.C. Busch, MD PhD, surgeon 
Department of Surgery, Academic Medical Centre,  
Meibergdreef 9, 1105 AZ Amsterdam, the 
Netherlands Phone: +31-20-5669111 
e-mail: o.r.busch@amc.uva.nl  

 
 
COLOPEC study protocol version 9.3 5-12-2016  
Protocol signature sheet 
 
Name 
Signature 
Date 
For non-commercial research, 
Head of Department: 
 
D. Legemate, MD PhD, Professor of 
Surgery 
 
 
Coordinating Investigator/Project 
leader/Principal Investigator: 
 
P.J. Tanis, MD PhD, oncological surgeon 
 
 
 
 
 
 

 
 
COLOPEC study protocol version 9.3 5-12-2016  
TABLE OF CONTENTS 
 
1. 
SUMMARY ..................................................................................................................... 9 
2. 
INTRODUCTION AND RATIONALE .............................................................................12 
2.1 
Standard care .........................................................................................................15 
2.2 
Motivation for intervention ......................................................................................16 
2.3 
Incidence ................................................................................................................18 
2.4 
Impact on clinical practice and healthcare system ..................................................18 
2.5 
Studies with similar designs. ..................................................................................20 
3. 
OBJECTIVES ................................................................................................................21 
4. 
STUDY DESIGN ...........................................................................................................21 
5. 
INVESTIGATIONAL PRODUCT ....................................................................................23 
5.1 
Name and description of investigational  product(s) ...............................................23 
5.2 
Summary of findings from clinical studies ...............................................................23 
5.3 
Potential benefits and risks of adjuvant HIPEC .......................................................27 
5.4 
Dosages, dosage modifications and method of administration ...............................28 
5.5 
Preparation and labelling of Investigational Medicinal Product and Drug 
accountability ....................................................................................................................29 
6. 
STUDY POPULATION ..................................................................................................31 
6.1 
Population (base): ..................................................................................................31 
6.2 
Inclusion criteria .....................................................................................................31 
6.3 
Exclusion criteria ....................................................................................................31 
6.4 
Sample size calculation ..........................................................................................33 
7. 
TREATMENT OF SUBJECTS .......................................................................................34 
7.1 
Standard care of the control arm ............................................................................34 
7.2 
Investigational product/treatment ............................................................................35 
7.3 
Escape medication .................................................................................................37 
8. 
METHODS ....................................................................................................................38 
8.1 
Main study parameter/endpoint ..............................................................................38 
8.2 
Secondary study parameters/endpoint ...................................................................38 
8.3 
Other study parameters ..........................................................................................39 
8.4 
Randomisation and treatment allocation .................................................................39 
8.5 
Study procedures ...................................................................................................40 
8.6 
Withdrawal of individual subjects ............................................................................42 
8.7 
Follow-up of subjects withdrawn from treatment .....................................................42 
8.8 
Termination of the study .........................................................................................42 
9. 
SAFETY REPORTING ..................................................................................................43 
9.1 
Section 10 WMO event ..........................................................................................43 
9.2 
AEs, SAEs and SUSARs ........................................................................................43 
9.3 
Annual safety report ...............................................................................................46 
9.4 
Follow-up of adverse events ...................................................................................47 
9.5 
Data Safety Monitoring Board (DSMB) ...................................................................47 
10. ANALYSES ...................................................................................................................48 
10.1 
Primary clinical study parameter(s) ........................................................................49 

 
 
COLOPEC study protocol version 9.3 5-12-2016  
10.2 
Secondary clinical study parameter(s) ....................................................................49 
10.3 
Economic evaluation ..............................................................................................49 
11. ETHICAL CONSIDERATIONS ......................................................................................52 
11.1 
Regulation statement .............................................................................................52 
11.2 
Recruitment and consent........................................................................................52 
11.3 
Objection by minors or incapacitated subjects ........................................................53 
11.4 
Compensation for injury .........................................................................................53 
11.5 
Incentives ...............................................................................................................53 
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .............................54 
12.1 
Handling and storage of data and documents ........................................................54 
12.2 
Amendments ..........................................................................................................54 
12.3 
Annual progress report ...........................................................................................55 
12.4 
End of study report .................................................................................................55 
12.5 
Public disclosure and publication policy ..................................................................55 

 
 
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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
ABR form, General Assessment and Registration form, is the application form 
that is required for submission to the accredited Ethics Committee (In Dutch, ABR 
= Algemene Beoordeling en Registratie) 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: Centrale 
Commissie Mensgebonden Onderzoek 
CUA 
Cost utility analysis 
CRC 
Colorectal cancer 
CR 
Cytoreductive surgery 
CV 
Curriculum Vitae 
DALY 
Disability adjusted life years 
DSMB 
Data Safety Monitoring Board 
EU 
European Union 
GCP 
Good Clinical Practice 
HIPEC 
Hyperthermic IntraPeritoneal chemotherapy 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IMP 
Investigational Medicinal Product  
IMPD 
Investigational Medicinal Product Dossier  
i.p. 
Intraperitoneal administration 
i.v. 
Intravenous administration 
METC  
 
Medical research ethics committee (MREC); in Dutch: medisch ethische toetsing 
commissie (METC) 
PC 
peritoneal carcinomatosis 
QALY 
Quality Adjusted Life-Year 
(S)AE 
(Serious) Adverse Event  
SPC 
Summary of Product Characteristics (in Dutch: officiële productinfomatie IB1-
tekst) 
Sponsor The sponsor is the party that commissions the organisation or performance of the 
research, for example a pharmaceutical company, academic hospital, scientific 
organisation or investigator. A party that provides funding for a study but does not 
commission it is not regarded as the sponsor, but referred to as a subsidising 
party. 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
Wbp 
Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens) 
WMO 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 

 
 
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1. SUMMARY 
Background:  
The peritoneum is the second most common site of recurrence in patients with colorectal 
cancer (CRC). Early detection of peritoneal carcinomatosis (PC) by imaging is difficult and 
adjuvant systemic treatment does not seem to affect peritoneal dissemination in contrast to 
haematogenous dissemination in the liver or lungs. Of all patients eventually presenting with 
clinically apparent PC, only a quarter have potentially curable disease. The curative option is 
cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CR/HIPEC), but the 
effectiveness depends highly on the extent of disease and is associated with a considerable 
complication rate. These clinical problems underline the need for effective adjuvant 
intraperitoneal therapy in high risk CRC patients in order to prevent the development of PC 
with treatment at a subclinical stage. 
 
Objectives: 
The aim is to determine the effectiveness of adjuvant HIPEC preceding routine adjuvant 
systemic therapy using i.p. oxaliplatin with concomitant i.v. 5-FU/LV following a curative 
resection of a T4 or intra-abdominally perforated colon cancer in preventing the development 
of PC in comparison to standard adjuvant systemic treatment alone. 
 
Study design:  
This will be a multicentre study in which eligible patients will be randomized to adjuvant 
HIPEC followed by adjuvant systemic chemotherapy in the experimental arm, or the standard 
adjuvant systemic chemotherapy alone in the control arm. Adjuvant HIPEC will be performed 
preferably simultaneously or within 10 days after resection of the primary tumour, either by 
laparoscopy or open approach, similar to the technique used for resection of the primary 
tumour. If adjuvant HIPEC cannot be performed within 10 days (i.e. complicated 
postoperative course), the procedure will be delayed until 5 to 8 weeks postoperatively. 
Subsequently, patients will receive routine adjuvant chemotherapy (CAPOX) within 3 weeks 

 
 
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from HIPEC. Diagnostic laparoscopy will be performed routinely after 18 months 
postoperatively in both arms of the study in patients without evidence of disease based on 
routine follow-up using CT imaging and CEA. If peritoneal carcinomatosis is found during 
staging laparoscopy, CR/ HIPEC will be performed in patients with a maximum of 5 involved 
regions and without evidence of systemic disease. 
 
Study population: 
Patients who underwent intentionally curative resection for a T4N0-2M0 or intra-abdominally 
perforated colon cancer. 
 
Intervention: 
Adjuvant HIPEC procedure: access to the abdominal cavity by laparoscopy or laparotomy 
under general anaesthesia, adhesiolysis if necessary, complete staging of the intra-
abdominal cavity, positioning of in- and outflow catheters, perfusion with a minimum of 2l 
isotonic dialysis fluid at a flow rate of 1-2l/min and an inflow temperature of 42-43˚C. Before 
the beginning of HIPEC, 5-fluorouracil 400 mg/m2 and leucovorin 20 mg/m2 will be 
administered intravenously to potentiate oxaliplatin activity. Oxaliplatin (460 mg/m2) is added 
to the perfusate after attaining at least 42 degrees inflow temperature with a total of 30 
minutes perfusion time.  
 
Outcomes:  
Primary endpoint is peritoneal recurrence-free survival at 18 months. Secondary endpoints 
are treatment related toxicity, incidence of PC, sensitivity of imaging to detect PC during 
follow-up, differences in patterns of dissemination (peritoneal plus or minus distant 
metastases), disease-free survival, overall survival, quality of life and costs. 
 
 
 

 
 
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Sample size: 
Based on the currently available literature, approximately 25% of colon cancer patients with a 
pT4 or perforated primary tumour will develop PC. Adjuvant HIPEC is expected to result in a 
60% relative risk reduction. To detect a 15% difference in PC rate at 18 months, a total 
number of 176 assessable patients (88 in each arm) are needed (alpha=0.05, power of 80%, 
drop-out 5%). 
 
Time schedule: 
Accrual of 176 patients in nine centres in the Netherlands is planned between January 2015 
and January 2017 with data analysis at the end of 2019. About 750 patients present each 
year with a pT4 and/or perforated colon cancer in the Netherlands yearly. Because the 
participating centres are all tertiary referral centres for PC with several referring hospitals 
each, timely accrual of 88 patients per year should be achievable. 
 

 
 
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2. INTRODUCTION AND RATIONALE 
 
Colorectal cancer (CRC) is the second most common cancer in the Netherlands. On the 1st 
of January 2010, there were 57,768 CRC patients with an incidence of 12,319 new patients 
in 2009 (www.nationaalkompas.nl). In 2010, 5,111 patients died of CRC. The incidence of 
CRC is increasing in the Netherlands and is expected to be 15,000 patients in 2015 
(www.oncoline.nl). The DALY for CRC is calculated to be 76,900 based on data from 2007 
and 
is 
therefore 
one 
of 
the 
diseases 
with 
the 
highest 
disease 
burden 
(www.nationaalkompas.nl). 
The peritoneum is the second most common site of recurrence in patients with colorectal 
cancer, accounting for 25 to 35% of all recurrences [1]. Synchronous peritoneal 
carcinomatosis (PC) is found in about 5% of the patients during the primary resection [2,3]. 
The incidence of metachronous PC is difficult to determine and ranges according to the 
literature between 4 and 19% [4]. The observed incidence of metachronous PC depends on 
the population characteristics (i.e. tumour stage), accuracy of imaging during follow-up, 
explorative relaparotomy of relaparoscopy rates during follow-up and autopsy rates. PC rates 
of up to 44% are reported during reoperation for CRC and in between 40 and 80% in autopsy 
series [4]. Because the clinical diagnosis of PC is much more difficult than the diagnosis of 
liver or lung metastases, it is likely that reported incidences of metachronous PC are 
underestimated. 
Peritoneal dissemination is due to local serosal involvement of the tumour and subsequent 
detachment of free intraperitoneal tumour emboli. Other etiological mechanisms of free intra-
abdominal tumour cells are leakage from transected lymphatic channels or blood vessels, or 
direct dissemination by surgical manipulation of the tumour [1,5].  
Important risk factors for peritoneal tumour seeding of CRC identified in the literature are 
advanced stage of the primary tumour (pT4), tumour perforation and obstruction, and 
positive cytology of peritoneal lavage [6-8]. Based on the literature, the risk of developing PC 
for the different subpopulations of colorectal cancer is 17-50% for pT4, 14-58% for perforated 

 
 
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tumours, 63% for resected local peritoneal nodules, 75% for patients with ovarian 
metastasis, and 23-50% for patients with positive peritoneal cytology [6,9-15]. 
PC of colorectal cancer origin is associated with a poor prognosis. Median survival is only 
about 5 months if untreated and has a reported range between 5 and 15 months if treated 
with palliative systemic chemotherapy, being significantly worse compared to survival rates 
after palliative systemic chemotherapy for non-peritoneal localisations [16-19]. Quality of life 
is often significantly impaired because of ascites and bowel obstruction [19]. Palliative 
interventions like percutaneous drainage of ascites, intestinal bypass or stoma formation are 
associated with substantial morbidity, restricted effectiveness, and costs. During the last few 
months until death, the patient often requires intensive palliative care at a hospital, nursing 
home, hospice or home care setting (www.pallialine.nl). This translates into a significant 
disease burden. 
In three quarter of the patients with PC of colorectal origin, only palliative treatment options 
remain at time of diagnosis. Less than half of the patients have sufficient clinical condition to 
tolerate systemic chemotherapy [20]. However, the effectiveness is restricted, even for 
modern chemotherapy regimens with or without targeted agents [17,18]. There seems to be 
a relative resistance of PC for systemic chemotherapy. In the remaining quarter of the 
patients without distant metastases and restricted peritoneal tumour load, cytoreductive 
surgery (CR) and HIPEC is an intentionally curative treatment option. A large number of 
phase II studies and two phase III trials have been published on CR/HIPEC, showing an 
improved survival in comparison with only systemic chemotherapy [16,21-32]. However, the 
effectiveness of CR/HIPEC highly depends on the extent of disease. If complete 
cytoreduction of PC is obtained, 5-year survival rates of 45% to 51% can be achieved in 
combination with HIPEC, but survival is significantly lower if not all visible tumour could be 
resected [33,34]. Furthermore, CR/HIPEC is associated with substantial morbidity, namely 
infectious complications (intra-abdominal abscesses, anastomotic leakage, enteric fistula, 
wound infection) and abdominal wall complications (hernias). 

 
 
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Because of the difficulties in treating PC at a clinically overt stage and the restricted 
sensitivity of imaging modalities to detect PC at an early stage, advancing the treatment to a 
subclinical stage may overcome the current problems in treating patients with PC of 
colorectal origin. In other words, effective adjuvant treatment to prevent development of PC 
in high risk CRC patients is warranted. 
Prognosis of PC is poor despite the administration of systemic chemotherapy, with median 
survival rates between 5 and 13 months based on four studies [13,16,35,36]. Similarly, i.v. 
administration of chemotherapy in the adjuvant setting does not seem to affect the 
occurrence of peritoneal recurrences. Intraperitoneal (i.p.) administration of chemotherapy 
has been used to treat or prevent PC from various primary malignancies [5,27,37-43]. From 
a pharmacological point of view, this is an attractive approach given the peritoneal-plasma 
barrier which allows for higher peritoneal cavity concentrations resulting in higher efficacy 
while systemic toxicity is not increased. 
In an attempt to prevent PC of CRC, i.p. 5-FU administration through a peritoneal catheter in 
the immediate postoperative period or as prolonged treatment up to 12 months has been 
used, as well as HIPEC using mitomycin-C or oxaliplatin [40,41,44-47]. The comparative 
studies are summarized in Table 1, with corresponding outcome data in Table 2. Cohort 
studies on adjuvant i.p. chemotherapy are summarized in Table 3, with corresponding 
outcome in Table 4. It can be concluded from these studies that i.p. chemotherapy seems to 
reduce intraperitoneal recurrence rates, and that even a survival benefit is suggested in 
studies using adjuvant HIPEC. These studies are subjected to significant bias and no 
definitive conclusions can be drawn based on these data. With regard to treatment related 
morbidity of adjuvant i.p. chemotherapy, these data as well as experience from the first 10 
patients included in a Dutch feasibility study reveal that adjuvant HIPEC is a well-tolerated 
intervention with no significant morbidity, which can be performed in a short stay setting 
[48,49]. This supports conducting a randomized trial to determine the oncological 
effectiveness of adjuvant HIPEC in addition to routine adjuvant systemic therapy. 
 

 
 
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2.1 Standard care 
According to the Dutch guidelines, adjuvant systemic chemotherapy in colon cancer is 
indicated for patients with node-positive disease (stage III) and can be considered in high risk 
stage II patients without MSI, including the following:  
- 
T4 tumour; 
- 
poorly differentiated,  
- 
perforation or obstruction at presentation,  
- 
less than 10 lymph nodes examined 
- 
 vascular invasion (oncoline.nl).  
The most commonly used adjuvant chemotherapy regimen in the Netherlands is 
capecitabine and oxaliplatin in 8 courses of each 3 weeks.  
Patients who already have PC but without evidence of systemic dissemination to other sites 
are candidates for CR/HIPEC, although the number of affected regions should not exceed 5 
of 7 defined abdominal regions. CR/HIPEC entails a median laparotomy form xyphoid to 
pubic bone, with resection of all visible tumour in the abdominal cavity (R1 resection) if 
technically achievable, or debulking with a residual tumour thickness of less than 2.5 mm. If 
necessary, involved organs such as bowel segments, uterus, ovaries, stomach, or spleen are 
resected, together with omentum and involved parts of the peritoneum. Subsequently, the 
abdominal wall is retracted using a so-called Colosseum approach with positioning of inflow 
and outflow catheters in the abdominal cavity. These are connected to a pump with heat 
exchange and a perfusate is added to the circuit. If the desired temperature has been 
reached, chemotherapy is added. After perfusion, intestinal anastomoses are constructed 
and the abdomen is closed. Analysis of Dutch CR/HIPEC experience revealed a median 
hospital stay of 16 days (95%CI 13-22) [50]. Grade 3 to 5 morbidity was 34%, of which 
anastomotic leakage, abscess and fistula were the most commonly observed, often requiring 
re-operation and ICU admission. Postoperative mortality was 3%. 

 
 
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Patients with PC who are not candidate for CR/HIPEC can be treated with palliative systemic 
therapy if the clinical condition is sufficient, or palliative interventions like drainage of ascites 
or relief of obstruction by intestinal bypass or stoma. 
 
2.2 Motivation for intervention 
The intervention consists of a single HIPEC procedure using i.p. oxaliplatin combined with 
i.v. 5-FU/LV, either using a laparoscopic or open approach, and performed simultaneous with 
primary tumour resection or in the early postoperative period (< 10 days or between 5-8 
weeks). 
From a pharmacological point of view, the intraperitoneal route for adjuvant treatment has 
the advantage of administering much higher doses of chemotherapy without increasing 
systemic toxicity due to the peritoneum-plasma barrier. Furthermore, hyperthermia 
potentiates the effect of certain cytotoxic agents. 
Although studies on adjuvant intraperitoneal administration of 5-FU in CRC patients at the 
end of the 20th century suggested a reduction of peritoneal recurrence rates, this did not 
uniformly translate into survival benefit [48]. In addition, repeated chemotherapy 
administration in an out-patient setting through peritoneal catheters was associated with 
discomfort and catheter related morbidity. This was the reason that the oncological 
community lost interest in the adjuvant i.p. treatment to prevent PC of CRC origin. 
Subsequently, HIPEC using mitomycin-C or oxaliplatin was shown to be effective in the 
treatment of macroscopic PC from CRC origin in addition to cytoreductive surgery. Based on 
the success of HIPEC as a combined procedure with cytoreductive surgery, initial small 
studies were conducted using HIPEC alone in the adjuvant setting[49,51-54]. These data are 
promising because of the suggested oncological effectiveness with minimal associated 
morbidity [48]. 
In addition to the conventional open approach, there is also the possibility to deliver HIPEC 
by a minimally invasive approach. If compared to an open procedure, laparoscopic HIPEC 

 
 
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avoids the risk and recovery time associated with a laparotomy while the temperature profiles 
and peritoneal perfusion flow rates are similar [55]. Experimental studies in pigs suggest 
even better penetration of chemotherapy in a closed abdomen probably due to increased 
abdominal pressure [56,57]. 
Timing of the adjuvant HIPEC procedure has been tailored to the individual patient within the 
COLOPEC trial. Both a simultaneous and a staged approach can be chosen. A theoretical 
disadvantage of a staged approach is the suggested phenomenon of residual cancer cells 
being encapsulated with fibrin, which probably make these cells less  accessible for 
chemotherapy at an interval of more than two weeks after surgery [28,58-60]. Therefore, it is 
often stated that HIPEC should ideally be performed simultaneously with primary tumour 
resection, although this is not an evidence based recommendation. Simultaneous adjuvant 
HIPEC is often not feasible because pT4 stage is only found at definitive pathology, HIPEC is 
not available at time of primary tumour resection in an emergency setting for a perforated 
tumour, or surgery is being performed outside a HIPEC centre. In order to make results from 
a RCT transferable to daily clinical practice in the end, the possibility of early postoperative 
HIPEC has been included in the study protocol. Staged HIPEC may be performed within 10 
days in case of adequate patient condition and logistics, or may be delayed to 5-8 weeks 
from primary resection. The theoretical advantage of staged adjuvant HIPEC is that healing 
of the anastomosis is not compromised by immunosuppression as a result of the 
administration 
of 
chemotherapeutic 
agents, 
and 
the 
more 
favourable 
logistics. 
Disadvantages of staged adjuvant HIPEC are the necessity of adhesiolysis, the risk of 
suboptimal distribution of chemotherapy in the abdominal cavity, and the potential delay of 
routine adjuvant systemic treatment.  
Considering the different chemotherapeutic agents, oxaliplatin and Mitomycin-C are both cell 
cycle independent alkylating agents, interfering with DNA and DNA-synthesis. Because of a 
large molecular weight, there is limited systemic absorption of both agents. The 
enhancement of cytotoxicity under hyperthermia and a maximal tissue penetration of 2 mm is 
also comparable. Although there are no randomized studies comparing oxaliplatin and 

 
 
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Mitomycin-C for CR/HIPEC, literature suggests an equal antitumour effectiveness [61]. The 
advantage of oxaliplatin is the absence of neutropenia and shorter perfusion time (30 versus 
90 minutes) compared to MMC. 
 
2.3 Incidence 
Colorectal cancer is the second most common cancer in men and second most common 
cancer in women. Approximately 13.000 new patients are diagnosed each year in the 
Netherlands, with an expected incidence of 15.000 in 2015.  The population with a high risk 
of PC after curative resection considered to be the potential candidate for the COLOPEC 
study can be partly extrapolated from the Dutch Surgical Colorectal Audit (www.dsca.nl). The 
number of patients with a pT4 and/or perforated colon cancer and an age below 75 years 
was 547 in 2009, 660 in 2010, 706 in 2011 and 867 patients in 2012. Although there seems 
to be an increase of this subgroup of patients, this may be explained by more completeness 
of registration in recent years of the DSCA. Not all potential candidates will eventually be 
eligible for adjuvant HIPEC because of co-morbidity or complicated postoperative course. 
Based on an estimated drop-out of 10%, the estimated number of eligible patients for the 
COLOPEC study in the Netherlands is about 750 each year. But in daily practice, this 
number will appear to be much lower because of unfamiliarity with relevant trials and logistics 
in several Dutch hospitals. 
 
2.4 Impact on clinical practice and healthcare system 
There needs to be a good balance between associated costs and morbidity on one hand and 
effectiveness on the other hand for an adjuvant treatment modality. For routine adjuvant 
systemic chemotherapy in colon cancer, an absolute survival benefit as low as 5% is 
considered to be worthwhile despite duration of treatment for 6 months with treatment related 
toxicity such as hand-foot syndrome. 

 
 
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Based on published incidences of PC between 14 and 58% for perforated CRC and between 
17 and 50% for pT4 stage, the estimated incidence of PC in the study population will be 
25%. The relative risk reduction in PC by adjuvant HIPEC in the comparative studies of 
Sammartino et al. was 82% [53]. The older randomized studies using i.p. 5-FU showed 
relative risk reductions of 78% and 62% [46,47]. Based on these data, a conservative 
expected relative risk reduction of adjuvant HIPEC is 60%. The expected advantage of the 
experimental intervention is therefore an absolute reduction of 15% in PC (from 25% to 
10%). 
As a consequence of a 15% absolute risk reduction, from each cohort of 100 patients, 85 
patients will undergo an additional treatment without any benefit. This is only acceptable if 
the associated morbidity is relatively low, which appears to be so based on systematic review 
of the literature and our own feasibility study [48,49]. 
Adjuvant HIPEC is expected to have a dual advantage. Prevention of PC will potentially 
reduce the application of CR/HIPEC. Secondly, part of advanced stage PC will be prevented, 
which would otherwise have led to palliative treatment. It is, however, difficult to predict the 
exact proportions of reduction in CR/HIPEC procedures or palliative treatment for advanced 
PC in the end based on the application of adjuvant HIPEC. 
With regard to the cost-effectiveness, additional costs of routine adjuvant HIPEC should be 
weighed against gained life years and reduced costs of patients in whom PC has been 
prevented to develop. A 15% reduction of peritoneal recurrence is expected to result in at 
least a 5% survival benefit, given the dismal prognosis associated with development of PC 
and based on an update of the study by Sammartino et al. [abstract HIPEC congress 
Amsterdam 2014]. Reduced costs may be related to less expensive treatment for clinically 
manifest PC, such as CR/HIPEC (approximately €50.000 per procedure) and palliative 
systemic treatment including expensive targeted agents such as bevacizumab (€2.400 per 
month per patient). Furthermore, reduced costs may be related to a reduced use of other 
palliative treatment modalities (ascites drainage, palliative surgery) and less need for 
palliative care in a hospital or other institutional setting, or at home.  

 
 
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2.5 Studies with similar designs. 
No similar studies are planned as far as our research group is aware of. Our research group 
is in close contact with the international HIPEC researchers and has organized the world 
congress on peritoneal surface malignancies to be held in October 2014 in Amsterdam. 
Therefore, we are well informed about current developments in this field. Also searching at 
www.clinicaltrials.gov did not reveal ongoing studies on early postoperative adjuvant HIPEC 
for patients with high risk colon cancer. 
There is one French randomized controlled trial that has just completed inclusion using a 
different approach in a slightly different patient population. This trial randomly assigned 
patients with local peritoneal disease at primary tumour resection, isolated ovarian 
metastases or perforated tumours to routine follow-up or second look laparotomy after 12 
months with ‘in principle’ HIPEC (NCT01226394) [62]. No data are available yet. A similar 
study design has been published by an American group [63], but this trial has been 
withdrawn prior to enrollment (NCT01095523). Another similar phase III trial is planned to 
start in October 2014 at the Zhejiang University, China, with second look laparotomy and 
HIPEC at 6 months, including also pT4 cancers in addition to the other three inclusion criteria 
of the French trial (NCT02179489). According to our opinion, this approach is essentially 
different because second look surgery with systematic HIPEC and cytoreduction on 
indication is not an adjuvant treatment approach. Furthermore, the patients to be included 
with local peritoneal disease or ovarian metastases have already developed PC. We 
consider these patients to be candidate for routine HIPEC outside a trial setting and feel that 
it is unethical to randomize these patients with a chance of not having effective treatment for 
proven PC. A third study from Naples, Italy, is a randomized phase II trial comparing routine 
follow-up with second look laparoscopy and HIPEC in case of PC at 6 months 
postoperatively for patients who underwent resection for mucinous colorectal cancer of any 
stage (I-III) (NCT01628211). 

 
 
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3. OBJECTIVES  
Primary aim of this study is to determine the oncological effectiveness of adjuvant HIPEC, 
using i.p. oxaliplatin with concomitant i.v. 5-FU/LV, following a curative resection of a T4 or 
intra-abdominally perforated colon cancer in preventing the development of PC in addition to 
the standard adjuvant systemic treatment. 
 
Secondary aims are: 
1. to determine the incidence of PC in pT4 and perforated colon cancer with metastatic 
patterns based on prospectively collected data and diagnostic laparoscopy at 18 
months as a golden standard during follow-up.  
2. to determine treatment related morbidity of open and laparoscopic adjuvant HIPEC 
3. to determine treatment related morbidity of simultaneous and staged adjuvant HIPEC 
(both early postoperative (0-10 days) as well as delayed (3-8 weeks))  
4. to determine several procedural characteristics of adjuvant HIPEC such as operating 
time, hospital stay, and re-admission rate 
5. to compare quality of life and costs of adjuvant HIPEC with standard adjuvant 
systemic treatment 
 
4. STUDY DESIGN 
This will be a multicentre study in which eligible patients will be randomized to adjuvant 
HIPEC followed by adjuvant systemic chemotherapy in the experimental arm, or adjuvant 
systemic chemotherapy alone in the control arm (flow diagram). Stratification factors will be 
tumour characteristic (T4 or perforation), surgical approach (laparoscopy or open) and age 
(<65 years or 65 years). Adjuvant HIPEC will preferably be performed simultaneous with 
resection of the primary tumour or within 10 days thereafter, either by laparoscopy or open 
approach, similar to the technique used for resection of the primary tumour. If adjuvant 
HIPEC cannot be performed within 10 days (i.e. complicated postoperative course, 
inflammatory response in patients with perforation), the procedure will be delayed until 5 to 8 

 
 
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weeks postoperatively. Subsequently, patients will receive routine adjuvant systemic 
chemotherapy according to local treatment protocols within 3 weeks from HIPEC, preferably 
as soon as the clinical condition allows for systemic therapy. Diagnostic laparoscopy will be 
performed routinely after 18 months postoperatively in both arms of the study in patients 
without evidence of disease based on routine follow-up using CT imaging and CEA. 
Laparoscopy enables accurate assessment of the primary endpoint of the study and may 
have therapeutic implications for patients in whom asymptomatic PC is proven by 
laparoscopically taken biopsies. These patients will subsequently be treated by CR/HIPEC 
according to the national guideline, with a switch to mitomycine-C in patients who underwent 
adjuvant HIPEC with oxaliplatin previously. This approach is supported by the increasing 
data in the literature on the value of second look surgery for high risk patients [64,65]. All 
relevant data during work up, management and follow up will be collected in an electronic 
case record form. Data will be documented in line with ‘Good Clinical Practice’ and Dutch 
legal requirements. 
Flow-diagram 
Curative intent treatment for T4N0-2M0 or perforated colon cancer
Exclusion criteria
· 
Postoperative complications that interfere 
with adjuvant  HIPEC within 8 weeks
· 
liver and/or lung metastases 
· 
pregnant or lactating women
· 
unstable or uncompensated respiratory or 
cardiac disease
· 
serious active infections
· 
other concurrent chemotherapy
RANDOMISATION
N=176
Group B 
Experimental treatment 
N= 88
Group A 
Standard treatment 
 N= 88
Adjuvant systemic chemotherapy (<12 weeks)
(local treatment protocol)
Registration phase
Randomisation phase
Adjuvant HIPEC 
(primary resection or <10 days or 5-8 weeks)
· 
IV; fluorouracil (400 mg/m2) and leucovorin (20 mg/m2)
· 
HIPEC, 30 minutes perfusion, laparoscopic or open; Oxaliplatin 
(460 mg/m2)
Study treatment
Adjuvant systemic chemotherapy 
(<3 weeks after HIPEC, <12 weeks after primary resection)
(local treatment protocol)
Diagnostic laparoscopy
 (18 months after surgery)
Primary resection
Primary resection
 

 
 
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5. INVESTIGATIONAL PRODUCT  
5.1 Name and description of investigational  product(s) 
All patients will receive the standard adjuvant systemic treatment according to the local 
institutional protocol, which mostly consists of capecitabine and oxaliplatin (CAPOX) or 5-FU 
and oxaliplatin (FOLFOX). Patients who randomize for HIPEC (group B)  will receive intra-
operative leucovorin 20 mg/m2 and 5-fluorouracil 400 mg/m2 systemically and intraperitoneal 
oxaliplatin 460 mg/m2 (maximal 920 mg) followed by standard adjuvant systemic treatment 
according to the local protocol. 
 
 
5.2 Summary of findings from clinical studies 
 
Prognosis of PC is poor despite the use of  systemic  chemotherapy, with disappointing 
median survival between 5 and 13 months based on four studies [13,16,35,36]. Similarly, IV 
administration of chemotherapy in the adjuvant setting does not seem to affect the 
occurrence of peritoneal recurrences. 
Literature on intraperitoneal (i.p.) administration of chemotherapy in the adjuvant setting after 
curative resection of colorectal cancer was systematically reviewed [48]. A total of 12 studies 
were included. The studies were categorized as comparative studies (n=7) and prospective 
cohort studies (n=5) and displayed in Table one to four. Among the comparative studies, four 
randomized controlled trials (RCT) [40,41,46,47], two non–randomized comparative studies 
[6,54], and one case control study were identified [53]. 
The oldest of the selected articles was published in 1985 [47], and the most recent 
publication dated from 2012 [53]. The largest comparative study included 267 patients [41], 
and the largest cohort study included 87 patients [52]. In total, adjuvant (H)IPEC was 
administered in 463 patients. Five studies confined their inclusion to colon cancer patients 
only [41,44-46,53,66], whereas most studies did not exclude rectal cancer patients. One 
study included only rectal cancer patients [52].  
 

 
 
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Criteria for the inclusion of patients. 
Nodal positive disease and/or T4 tumours were reported as inclusion criteria in most studies 
[41,44-47,51,52]. Three studies included all patients with T3 or T4 tumours, regardless of 
nodal status [53,54,66]. One study included all electively operated patients, with exclusion of 
patients with stage I disease [40]. Additional inclusion criteria were malignant obstruction or 
perforation [44,47,51,53], positive peritoneal lavage [6,51], CRC under the age of 30 [47], 
and signet ring cell or mucinous tumours [53]. 
 
(H)IPEC agents and combinations with systemic treatment. 
5FU was used as single chemotherapeutic agent for intraperitoneal use in five studies 
[40,41,45,47,54]. Intraperitoneal LV was used in combination with a fluoropyrimidine analog 
(e.g. 5FU or floxuridine) in three studies [44,46,66], a combination of intraperitoneal 5FU and 
intravenous LV was used in one study [40], and three studies used concurrent intraperitoneal 
and intravenous 5FU administration either combined with intravenous LV or oral levamisole 
[44,46,66]. MMC was exclusively used during (H)IPEC in two studies [6,51], either MMC or 
oxaliplatin in one study [54], and exclusively oxaliplatin in another study [53]. Lygidakis et al. 
described the use of 5FU, oxaliplatin, LV, irinotecan, and mitomycin, but chemotherapy 
schedules were not further specified [52].  Hyperthermia was used to potentiate the effect of 
MMC or oxaliplatin in all studies, except for the study by Noura et al. [6] The effect of 
intraperitoneal oxaliplatin was further potentiated by intravenous administration of 5FU/LV 
just before the start of the (H)IPEC procedure.  
Fluoropyrimidine or oxaliplatin based adjuvant systemic treatment was given in addition to 
adjuvant (H)IPEC in seven studies (Table 1 and 3). (H)IPEC was not followed by adjuvant 
systemic therapy in four studies [40,41,45,47]. In one of these studies, a combined adjuvant 
treatment schedule was used of repeated ambulatory intraperitoneal 5FU/LV administration 
and low doses of radiotherapy [45]. In one additional study the use of systemic treatment 
after adjuvant HIPEC was not mentioned [51]. 
 

 
 
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Tolerance, morbidity and mortality of (H)IPEC.  
The tolerance, morbidity and mortality for the different strategies is summarized in Table 2 
and 4. Intolerance of intraperitoneal treatment was reported as dose limiting events, failure to 
complete the treatment, severe treatment associated side effects, and grading of (H)IPEC 
toxicity. Various grading systems or definitions, such as postoperative complications, serious 
complications, and life threatening side effects were used for the description of morbidity.  
Mortality was defined as treatment related mortality, in hospital mortality or mortality within 30 
days.  
Complications like infection [66], chemical peritonitis [45,47], diabetes [47], bowel perforation 
[66], abdominal discomfort and pain [41,46,47], intestinal obstruction or ileus [40] and 
intestinal poliposis [47] were specifically associated with repeated IPEC via intraperitoneal 
catheters. Seymour et al. studied the morbidity of repetitive intraperitoneal treatment with 
5FU/LV by escalating the treatment frequency. The authors found that a weekly frequency 
was not tolerated; mostly due to abdominal pain [66]. Specific complications related to 
operative (H)IPEC were catheter or port site problems (such as cellulitis) [6,51] pancreatitis 
[53,54], and haematological toxicity with bone marrow aplasia in two patients from one study 
using a relative high dose of mitomycin-C [51]. Anastomotic failure was not associated with 
(H)IPEC in any of the studies. 
Scheithauer et al. reported a severe adverse reaction rate of 13% in patients who received 
repeated IPEC with 5FU/LV compared to 3% in patients that did not receive intraperitoneal 
treatment [46]. This was the only study in which (H)IPEC showed a significantly higher rate of 
treatment related side effects compared to controls. However, the authors concluded that 
treatment associated side effects were infrequent and generally mild. 
Graf et al. compared repeated IPEC using 5FU with repeated IPEC using a placebo [40]. 
Two patients in the 5FU group were diagnosed with localized peritonitis versus no patients in 
the placebo group. However, intestinal obstruction requiring surgery and wound infection 
occurred more often in the placebo group (1 vs. 2 and 4 vs. 9, respectively). The overall rate 

 
 
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of post-operative complications was not significantly different between the 5FU and placebo 
group.  
In the study of Tentes et al., HIPEC with MMC or oxaliplatin simultaneously with the primary 
resection was compared to early postoperative repeated IPEC using 5FU via a peritoneal 
catheter [54]. Overall complications occurred significantly more often in the repeated IPEC 
group. In addition, a significant difference in hospital mortality rate was reported with nine out 
of 67 (13%) deaths in the repeated ambulatory IPEC group compared to one out of 40 (3%) 
in the intra-operative HIPEC group. Causes of death were not provided.  
 
Survival and incidence of PC in comparative studies. 
Oncological outcome parameters were analyzed in six out of seven comparative studies 
(Table 2) [6,41,46,47,53,54]. All three survival studies on operative (H)IPEC reported a 
significant impact on either overall or disease-free survival [6,53,54]. An absolute difference 
in 5-year cancer specific survival of 44.8% was found by Noura et al.[6]. Tentes et al. 
reported a significant difference in 3-year overall survival rate of 31.0%, in favour of the 
operative (H)IPEC group compared to the IPEC group (100% vs. 69%)[54]. Sammartino et 
al. showed a difference in median disease-free survival of 14.9 months in favour of the 
operative (H)IPEC group (36.8 vs. 21.9 months)[53]. From the studies that compare repeated 
ambulatory IPEC with no intraperitoneal chemotherapy, Vaillant et al. and Scheithauer et al. 
described absolute differences in overall survival rates of 6.0% and 18.0% respectively in 
favour of the IPEC groups, but these were not tested for significance [41,46]. The study by 
Sugerbaker et al. revealed no significant difference in overall survival [47].  
Five studies compared the peritoneal recurrence rate after (H)IPEC with a control group 
[6,41,46,47,53]. Peritoneal recurrence rates varied between 4% and 91%. A significant 
difference in the incidence of PC in favour of adjuvant (H)IPEC was found in four studies 
(Table 2) [6,46,47,53]. Vaillant et al. reported a difference in the incidence of PC of 2.0% 
between the treatment and control group but this was not tested for significance [41]. 
 

 
 
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5.3 Potential benefits and risks of adjuvant HIPEC  
A potential benefit of adjuvant HIPEC is an expected 60% relative risk reduction in PC. As a 
consequence, survival is expected to increase with the use of adjuvant HIPEC in comparison 
to treatment with standard adjuvant systemic chemotherapy alone [48]. 
 
However, treatment related morbidity and mortality of adjuvant i.p. chemotherapy are 
potential risks. Potential adverse reactions of adjuvant HIPEC using oxaliplatin by a 
laparoscopic or open approach are wound infection, intraabdominal abscess formation, 
fascial dehiscence, bowel perforation due to adhesiolysis, delayed gastric emptying, ileus, 
chemical peritonitis and haematological toxicity. A systematic review and meta-analysis [48] 
as well as experience from the first 10 patients included in a Dutch feasibility study reveal 
that adjuvant HIPEC is a well-tolerated intervention with no significant morbidity [48,49]. 
 
Another potential risk of adjuvant HIPEC is a possible delay in the administration of adjuvant 
systemic chemotherapy. A meta-analysis of Biagi et al suggests that a delay to initiation of 
adjuvant chemotherapy decreases overall survival [67]. However, outcome of this analysis is 
biased by the effect of a patient’s postoperative performance on time to adjuvant 
chemotherapy. Also, the chemotherapy used in the reviewed trials did not contain oxaliplatin 
and it is unknown whether the results can be extrapolated to oxaliplatin containing schemes. 
Another limitation of this study is that rates of completion and dosage reduction of adjuvant 
chemotherapy have not been reported. In the COLOPEC-trial, adjuvant HIPEC will preferably 
be performed during the primary resection or within ten days. Standard adjuvant 
chemotherapy is unlikely to be postponed by adjuvant HIPEC in these patients. When the 
HIPEC-procedure is yet 5-8 weeks postponed, this is in most cases due to a patient’s (poor) 
postoperative performance. Poor postoperative performance itself would also delay systemic 
chemotherapy. The staged HIPEC-procedure is thus expected to cause a relative delay only. 
Furthermore, logistics will be optimized based on experiences from our feasibility trial [68] in 
order to reduce the time between staged adjuvant HIPEC and start of systemic 

 
 
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chemotherapy. This will be achieved by early consultation of the medical oncologist and 
planning of systemic chemotherapy administration in advance. Finally, we recently switched 
from mitomycin-C to oxaliplatin as first choice chemotherapeutic agent for HIPEC in CRC 
patients in the Netherlands. There will be some systemic exposure to oxaliplatin during 
HIPEC and a potentiating dose of 5FU/LV will be given systemically. Therefore, systemic 
treatment already starts at time of adjuvant HIPEC, although in a suboptimal dose.   
 
5.4 Dosages, dosage modifications and method of administration 
The chemotherapy during oxaliplatin-HIPEC consists of  a intravenous phase with  
leucovorin 20 mg/m2  (maximum 40 mg) and  5-fluorouracil 400 mg/m2 (maximum 800 mg) 
and an intraperitoneal phase with oxaliplatin 460 mg/m2 (maximal 920 mg). These three 
cytostatics are ordered one day in advance.  
 
The HIPEC procedure will be performed as outlined below. 
 
1. 
Abdominal exploration using an open or laparoscopic approach 
2. 
30 minutes before HIPEC, at least one inflow catheter in Douglas pouch 
and one outflow catheter in the right subphrenic space is inserted and 
connected to the perfusion system. 
3. 
30 min before HIPEC; the surgical gloves are changed.  
4. 
25 min before HIPEC; leucovorin 20 mg/m2 in 100 cc of NaCl (0.9%) is 
intravenously administrated in 15 minutes by the anesthesiology personnel. 
5. 
10 minutes before HIPEC; 5-fluorouracil 400 mg/m2 m2 in 100 cc of NaCl 
(0.9%) is intravenously administrated in 10 minutes by the anesthesiology 
personnel. 
6. 
Simultaneous with the administration of intravenous cytostatics, the 
abdominal cavity is filled with Dianeal©  peritoneal dialysis solution (Baxter, 

 
 
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Peritoneal dialysis solutions, USA; Glucose 1.36 mg/100ml and is heated to 
42°C (minimal flow 2L/min) 
7. 
After completion of the intravenous 5-fluorouracil and reaching desired 
temperature and flow, complete dose of Oxaliplatin (460 mg/m2) delivered 
in 50 cc syringes (concentration of 5 mg/ml) is added to the circuit in a 
single bolus by the perfusionist. 
8. 
Perfusion for 30 minutes from time oxaliplatin was added to the perfusate. 
9. 
After completion of the perfusion, the perfusion fluids are aspirated and 
collected together with all used materials following the local protocol of 
chemotherapy waste collection and disposal 
10. 
Reconstruction with bowel anastomoses if indicated. Closure of the 
abdomen. The catheter in Douglas pouch is left in place as postoperative 
drainage. 
11. 
All body excretions are collected as chemotherapy contaminated as long as 
the patient is admitted up to 7 days postoperatively. 
 
5.5 Preparation and labelling of Investigational Medicinal Product and Drug 
accountability 
This is a pragmatic clinical trial. All HIPEC centres in the Netherlands are switching from 
mitomycin-C to oxaliplatin as standard chemotherapeutic agent for CR/HIPEC procedures or 
have already done so. Therefore, oxaliplatin-HIPEC will become standard of care for CRC in 
the Netherlands from start of the COLOPEC trial in January 2015. For this reason, the 
HIPEC medication will be used from commercial stock and preparation and labelling will be 
performed on a patient named basis within the hospital pharmacy of each HIPEC centre. 
Therefore, no specific labelling for research purposes will be performed for the IMPs. . A 
certified monitor will be installed and a monitoring program is drafted in collaboration with the 
Clinical Research Unit of the Academic Medical Centre. The monitor will check adherence to 

 
 
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GCP guidelines and in particular the administration of serious adverse events and drug 
accountability registration. The monitor reports to the steering committee. 
 
 

 
 
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6. STUDY POPULATION  
6.1 Population (base): 
Patients diagnosed with adenocarcinoma of the colon and either one of the two 
following risk factors for PC or both will be considered for inclusion: 
· 
T4N0-2M0 (stage T4 stage, either consisting of obvious clinical T4 stage 
based on preoperative imaging or intraoperative findings, or pathological T4 
stage) 
· 
Primary tumour presenting with perforation being curatively resected (N0-
2M0 stage) 
 
6.2 Inclusion criteria 
 
· 
age between 18 and 75 years 
· 
Intention to start standard adjuvant systemic therapy 
· 
adequate clinical condition to undergo simultaneous HIPEC or re-laparoscopy 
or re-laparotomy with HIPEC within either 10 days or between week 5-8 from 
primary resection 
· 
written informed consent 
· 
white blood cell count of at least 3000/mm3, platelet count of at least 
100.000/mm3  (< 3 months before surgery) 
· 
no bleeding diathesis or coagulopathy 
· 
normal creatinine or creatinine clearance of at least 50 ml/min (< 3 months 
before surgery) 
 
6.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 

 
 
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· 
postoperative complications that interfere with adjuvant HIPEC within 8 
weeks (i.e. persisting intra-abdominal abscess, significant fascial 
dehiscence, enteric fistula) 
· 
no intention or indication to start standard adjuvant systemic therapy 
· 
non-curative intent treatment 
· 
liver and/or lung metastases 
· 
pathological T4N0 with microsatellite instability (or MMR deficiency based 
on immunohistochemistry )  
· 
pregnant or lactating women 
· 
unstable or uncompensated respiratory or cardiac disease 
· 
serious active infections 
· 
other concurrent chemotherapy 
· 
hypersensitivity to fluorouracil, folinic acid or another substance of 
leucovorin or oxaliplatin 
· 
stomatitis, ulceration in the mouth or gastrointestinal tract.  
· 
severe diarrhea  
· 
severe hepatic and / or renal dysfunction.  
· 
plasma bilirubin concentrations greater than 85 μmol/l (measurement only 
necessary if indicated)  
· 
pernicious anemia or other anaemias due to vitamin B12 deficiency. 
· 
peripheral sensory neuropathy with functional impairment. 

 
 
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6.4 Sample size calculation 
 
Approximately 25% of CRC patients with a pT4 or perforated primary tumour is suspected to 
develop PC. This is based on reported incidences of PC between 14 and 58% for perforated 
tumours [10,69,70] and between 17 and 50% for pT4 stage [3,13,71]. Reported incidences 
may have been underestimated because of the inaccuracy of routine follow-up examinations 
to detect PC and incomplete autopsy rates of patients who died of CRC. Adjuvant HIPEC is 
expected to result in a 60% relative risk reduction in peritoneal recurrence based on the 
currently available literature. The relative risk reduction in a comparative study of 25 patients 
undergoing prophylactic HIPEC compared to a 1:2 matched control group was 82% [53]. 
Older randomized studies using i.p. 5-FU showed relative risk reductions of peritoneal 
recurrence of 78%[72] and 62% in favour of the i.p. chemotherapy groups [73]. 
To detect an absolute 15% difference in PC recurrence-free survival at 18 months (90% 
peritoneal recurrence-free under HIPEC plus systemic chemotherapy against 75% peritoneal 
recurrence free under systemic chemotherapy), a total number of 176 patients (88 patients 
per arm, with at least 88 assessable patients in the experimental arm) is needed (Kaplan-
Meier, one-sided, alpha=0.05, power of 80%, drop-out 5%). Actually, the power may even be 
higher, because the calculation ignores longer follow-up for the patients who have been 
included early on in the study. The term ‘assessable patient’ refers to a patient that can be 
evaluated regarding the study aim (i.e. in the experimental arm it means that a patient indeed 
received adjuvant HIPEC.).  
 
 

 
 
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7. TREATMENT OF SUBJECTS 
7.1 Standard care of the control arm 
Treatment in the control arm of the COLOPEC trial is in accordance with the current national 
guideline for adjuvant chemotherapy in colon cancer patients (www.oncoline.nl). Adjuvant 
intraperitoneal chemotherapy is currently not given to colon cancer patients with a high risk 
for peritoneal metastasis in the Netherlands. First line adjuvant systemic chemotherapy for 
colon cancer consists in the Netherlands of 6 months treatment with capecitabine and 
oxaliplatin (CAPOX) every 3 weeks or 5-FU and oxaliplatin (FOLFOX) every 2 weeks. 
Adjuvant chemotherapy is preferably started within 6-8 weeks after primary surgery and at a 
maximum of 12 weeks after primary resection.  
Follow-up will be performed routinely according to the national guideline during the first 18 
months. Patients who already developed recurrent disease during this time interval will be 
treated accordingly. In patients who have no clinical signs of recurrent disease at 18 months 
on CT scan of the thorax and abdomen in combination with non-elevated CEA levels, 
diagnostic laparoscopy will be performed. Patients with a negative laparoscopy will continue 
routine follow-up for at least 5 years, while patients with proven peritoneal recurrence found 
during laparoscopy will subsequently be treated according to the national guideline. 
Patients fulfilling the criteria for CR/HIPEC will be treated accordingly using oxaliplatin as 
intraperitoneal chemotherapeutic agent. The first line treatment for patients with 
pathologically proven PC from colon carcinoma who do not qualify for CR/HIPEC is systemic 
therapy. The application of systemic therapy depends on the comorbidity and the clinical 
condition of the patient. Palliative relief of symptoms related to ascites or obstruction can 
most often be achieved by (minimally invasive) interventions such as percutaneous drainage, 
endoscopic stent placement or creation of a diversion ostomy (www.pallialine.nl).     
 
 
 

 
 
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7.2 Investigational product/treatment 
Treatment in the experimental arm consists of adjuvant HIPEC followed by standard 
systemic chemotherapy. Timing of adjuvant HIPEC is tailored to the different clinical entities 
within the study population. Patients with obvious clinical T4 stage can be preoperatively 
asked for informed consent with simultaneous HIPEC if randomized in the experimental arm. 
If patients are randomized postoperatively based on intra-operative findings, early staged 
adjuvant HIPEC is preferably performed as soon as possible after primary resection but at a 
maximum of 10 days. When early postoperative HIPEC is not feasible, delayed staged 
adjuvant HIPEC will be performed in week 5 to 8 from primary resection. Staged HIPEC can 
be performed either by a laparoscopic or open approach to the discretion of the surgeon. In 
order to minimize delay in adjuvant systemic treatment, patients scheduled for delayed 
adjuvant HIPEC  will preoperatively be seen by the medical oncologist to plan the adjuvant 
systemic chemotherapy within three weeks after the adjuvant HIPEC. 
 
Laparoscopic adjuvant HIPEC 
The patient is in French position on a bean bag under general anesthesia with prophylactic 
antibiotics. For a staged procedure, open introduction of a 10-12 mm trocar in the left upper 
quadrant is performed and a CO2 pneumoperitoneum is induced. Additional trocars of 10-12 
mm are placed under direction vision in order to enable complete dissection of adhesions. In 
case of simultaneous laparoscopic HIPEC, minimally invasive access has already been 
obtained for the purpose of resection of the primary tumour without the need for adhesiolysis. 
The abdominal cavity is thoroughly inspected, including the Douglas pouch, the 
subdiaphragmatic spaces, the paracolonic gutters, and the entire small bowel. One 
multiperforated inflow catheter is placed through a 10-12 mm port in Douglas pouch. One 
multiperforated outflow catheter is placed in the right upper quadrant and positioned with the 
tip in the right subdiaphragmatic space. The patient’s body temperature will be monitored in 
the oesophagus. All trocars are tightly fixed to the skin to avoid fluid leakage during the 

 
 
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procedure. Additionally, trocars are kept in an upright position with sutures connected to the 
trocar, which run over an Omnitract system and attached to a clamp as counter weight. 
Perfusion by an autoregulated pump system will be started with a minimum of 2l isotonic 
dialysis fluid at a flow rate of 1-2l/min and an inflow temperature of 42-43˚C. Before the 
beginning of HIPEC, fluorouracil 400 mg/m2 and leucovorin 20 mg/m2 will be administered 
intravenously to potentiate oxaliplatin activity. After attaining at least 42 degrees inflow 
temperature, Oxaliplatin (460 mg/m2) will be added to the circuit in a single dose. The 
operating table will be rotated and tilted every 5 minutes, and the abdomen will be agitated 
throughout the infusion to allow homogeneous exposure of the peritoneal surfaces to the 
heated chemotherapy. After a total perfusion time of 30 minutes, the peritoneal fluid is totally 
suctioned and the abdomen is examined for evidence of tissue injury or bleeding. A suction 
drain will be left in Douglas pouch for 24 hours. The other port sites are closed in a standard 
fashion. Postoperative care after simultaneous HIPEC will be according to the primary 
colonic resection following an enhanced recovery programme. After staged laparoscopic 
HIPEC, patients are fully mobilized at day 1 with normal diet and will intentionally be 
discharged at day 1-3 if the institutional discharge criteria are fulfilled. Hematologic 
parameters will be determined at day 14, followed by start of systemic chemotherapy. 
 
Open adjuvant HIPEC 
Open adjuvant HIPEC can be performed simultaneously in patients undergoing primary  
open resection, and staged open adjuvant HIPEC can be performed by re-laparotomy in 
patients who underwent primary open CRC resection. The decision to perform staged open 
or laparoscopic HIPEC in case of prior open resection will be left to the discretion of the 
surgeon. Besides the access to the peritoneal cavity, the procedure is similar to the 
laparoscopic approach as described above. Preferably, a closed perfusion is performed 
rather than a Colosseum technique to have similar pharmacokinetics as a laparoscopic 
approach. After positioning of the in- and outflow catheters, the abdomen will then be closed 
and subsequently perfusion will be started. Postoperative care is similar to the laparoscopic 

 
 
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approach with an anticipated day of discharge between day 2 to 5 if discharge criteria are 
fulfilled. Hematologic parameters will be determined at day 14, followed by start of systemic 
chemotherapy. 
 
Follow-up after adjuvant HIPEC 
Follow-up will be performed routinely according to the national guideline during the first 18 
months. Patients who already developed recurrent disease during this time interval will be 
treated accordingly. In patients who have no clinical signs of recurrent disease at 18 months 
on CT scan of the thorax and abdomen in combination with non-elevated CEA levels, 
diagnostic laparoscopy will be performed. Patients with a negative laparoscopy will continue 
routine follow-up for at least 5 years, while patients with proven peritoneal recurrence found 
during laparoscopy will subsequently be treated according to the national guideline. 
Patients who develop peritoneal recurrence after oxaliplatin based adjuvant HIPEC and fulfil 
the criteria of CR/HIPEC, mitomycin will be used as chemotherapeutic agent for re-HIPEC. 
The first line treatment for patients with pathologically proven PC from colon carcinoma who 
do not qualify for CR/HIPEC is systemic therapy. The application of systemic therapy 
depends on the comorbidity and the clinical condition of the patient. Palliative relief of 
symptoms related to ascites or obstruction can most often be achieved by (minimally 
invasive) interventions such as percutaneous drainage, endoscopic stent placement or 
creation of a diversion ostomy (www.pallialine.nl). 
 
 
7.3 Escape medication  
Best supportive care for treatment-related symptoms will be offered as needed to all patients 
in this study. 
 
 

 
 
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8. METHODS 
8.1 
Main study parameter/endpoint 
The primary endpoint of the study is peritoneal recurrence-free survival at 18 months 
determined by CT and if negative by laparoscopy. Although 3-year disease free survival (3-
yr-DFS) using CT imaging is a commonly used endpoint in adjuvant setting, laparoscopy is 
more appropriate in this trial because of the restricted sensitivity of imaging modalities to 
detect PC at an early stage. Also, second look surgery is increasingly applied in patients at 
high risk of developing PC in- and out-side trial setting. Furthermore, evaluation at 18 months 
provides us with early data on the effectiveness of adjuvant HIPEC, as required by the Dutch 
government to decide on the coverage of adjuvant HIPEC by health insurance companies. It 
is likely that a significant reduction in peritoneal recurrence rate at 18 month will eventually 
translate into an overall survival benefit given the worse prognosis associated with peritoneal 
dissemination. 
 
8.2 
Secondary study parameters/endpoint 
Secondary endpoints of the COLOPEC trial are: 
· Treatment related toxicity of adjuvant HIPEC, including 30-day complication rate, re-
intervention rate, and re-admission rate. 
· Hospital stay for simultaneous and staged HIPEC, either open or laparoscopic 
· Incidence of PC 
· 
Sensitivity of imaging to detect PC during follow-up, using laparoscopy as a golden 
standard 
· Inter- and intravariability amongst radiologist detecting PC using CT-imaging.  
· Differences in patterns of dissemination (peritoneal plus or minus distant metastases) 
· Disease-free survival 
· Overall survival 
· Quality of life 

 
 
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· Costs 
· Costs per year free of PC 
· Costs per quality adjusted life year 
 
 
8.3 
Other study parameters  
A side study of the COLOPEC trial is:  
 
Molecular prognostic parameters; Tissue of primary tumours (and their metachronous 
peritoneal metastasis) will be collected. RNA and protein levels of different biomarkers will be 
evaluated by microarray/ real time PCR, western blot and immunohistochemistry in order to 
identify prognostic molecular parameters to better select colon cancer patients who have a 
‘high risk’ of developing peritoneal metastases in the future, providing evidence-based 
selection criteria for those who might benefit from adjuvant HIPEC. 
 
 
8.4 Randomization and treatment allocation 
Suitable patients will be approached for entry into the study at the surgical outpatient clinics 
or during hospital admittance. The rationale for the study is explained to the patient. A written 
patient information sheet is provided and patients will be given the opportunity to ask 
questions. After a sufficient reflection period, the willing patients are asked to sign the 
consent form. Once patient eligibility is confirmed, the patient may be consented for 
participation.  Written informed consent is taken by surgeons, surgical registrars or trained 
research nurses prior to the primary resection. When consent has been obtained, the original 
form is kept in the study file and a copy is given to the patient. Baseline data as well as 
baseline questionnaires are collected. 

 
 
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Randomisation will take place after written informed consent has been obtained. Due to 
logistic issues, randomization can also take place in case patients orally confirm that they 
have signed or will sign the consent form. Patients will be randomised between standard 
adjuvant systemic chemotherapy (control arm) and adjuvant HIPEC followed by standard 
adjuvant systemic chemotherapy (intervention arm) in a 1:1 ratio. Randomisation will be 
performed by a member of the study team at the site pre-operatively, during the primary 
resection or thereafter. Randomisation will be performed by a central automated 
randomisation using the trial website, with stratification for tumour characteristic (T4 or 
perforation), surgical approach (laparoscopy or open) and age (<65 years of  65 years). The 
allocated treatment will be confirmed by e-mail within one working day. The allocation of 
treatment is not blinded to the patient or outcome assessor. Randomized patients will be 
assigned a sequential subject number. A log of the assigned subject numbers will be 
maintained by each site.  
 
8.5 Study procedures 
Standard care and the intervention of the experimental arm are described in paragraph 3. 
During the operative procedure, information about the surgical procedure will be collected. 
Postoperatively, adverse events and reintervention will be registered. In addition, information 
regarding the duration of pre- and postoperative hospitalization and inpatient resource 
utilization will be collected. During the entire postoperative period, concomitant medications, 
adverse events, procedures and adjuvant therapies will be reviewed and documented. 
Blood testing for hematologic toxicity of adjuvant HIPEC will be performed at day 14. During 
routine outpatient clinic visits for oncological follow-up at 3, 6, 12, 18, 24, 36, 48 and 60 
months, disease recurrence will be checked. A working window of 15 working days is 
allowed for all follow-up moments. In addition, at 18 months postoperatively, a diagnostic 
laparoscopy is performed to check for PC in both arms of the study if there are no signs of 
peritoneal recurrence by routine follow-up examinations including abdominal CT. This 

 
 
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diagnostic laparoscopy is currently no standard treatment according to the national guideline, 
although second look surgery is increasingly applied in patients at high risk of developing PC 
in- and out-side trial setting. During the 18 months diagnostic laparoscopy, a 
pneumoperitoneum is installed with insertion of additional 5-12 mm trocars as appropriate for 
adhesiolysis and careful inspection of all abdominal regions, including the local resection 
site. When PC is encountered, appropriate treatment is given in accordance with patient 
preferences and current treatment protocols (www.oncoline.nl) ( i.e . systemic treatment, CR/ 
HIPEC). When applicable, cytoreduction with HIPEC can be performed in both treatment 
groups (adjuvant HIPEC/ adjuvant chemotherapy). Generic and cancer-specific quality of life 
assessments will be done with EQ-5D-5L and EORTC QLQ-C30 and CR-29 questionnaires 
respectively. For the purpose of economic evaluation, the iMTA Medical Consumption 
Questionnaire and iMTA Productivity Cost Questionnaire, adapted to the current study 
setting and target population, will be used at quarterly intervals during follow-up. The 
questionnaires will be sent to the patients’ home addresses, accompanied by a return 
envelope provided with postage stamps and the address of the hospital.  
 All medical or surgical interventions and or re-operations or any procedure to treat an 
adverse event will be collected. Major violations of the protocol will be recorded. 
For procedures and data sources related to costs, please see under ‘Economic evaluation’ in 
the Analyses section below. The data that will be collected are displayed in appendix 1. 
 

 
 
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8.6 Withdrawal of individual subjects 
Subjects can leave the study at any time and for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study if he/she 
fails to comply with the study requirements or if the investigator feels it is in the best interest 
of the subject to discontinue participation. Reason for withdrawal or early termination will be 
documented and no further study assessments will be performed after the subject has 
withdrawn. 
 
8.7 Follow-up of subjects withdrawn from treatment 
Patients whom have withdrawn from the study but are still willing in participating in the follow-
up will be followed according to the specifications of the patient.  
 
An excessive rate of withdrawals can render the study uninterpretable. If more than 10% of 
patients withdraw from the study after 20% of patients have been included, the study will be 
terminated for being unfeasible. Based on reasons of withdrawal the study protocol will be 
amended if necessary. 
 
8.8 Termination of the study 
 
The entire clinical investigation will be terminated if a serious treatment-related adverse 
event occurs, making it impossible to recruit new patients or to continue the treatment of 
patients already recruited for medical or ethical reasons. The clinical investigation in an 
individual patient will be terminated in case of 
1. insufficient compliance  
2. a patients request 
3. investigators request because of the onset of life-threatening adverse event.  
4. changes in health status incompatible with continued participation in the clinical 
investigation, as judged by the clinical investigator. 

 
 
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9. SAFETY REPORTING 
9.1 Section 10 WMO event 
 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if 
there is sufficient ground that continuation of the study will jeopardise subject health or 
safety.  The sponsor will notify the accredited METC without undue delay of a temporary halt 
including the reason for such an action. The study will be suspended pending a further 
positive decision by the accredited METC. The investigator will take care that all subjects are 
kept informed.  
 
9.2 AEs, SAEs and SUSARs 
9.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject during the 
study, whether or not considered related to the HIPEC procedure. All adverse events 
regardless of degree or causality with a severity degree of ≥ 2 (NCI-CTCAE) reported 
spontaneously by the subject or observed by the investigator or his staff, from the start of the 
study until one month after the last day of adjuvant systemic chemotherapy will be recorded. 
Incomplete data on severity and causality will not be retrospectively obtained. Because 
adjuvant chemotherapy is standard of care therefor not relevant to analysis of study 
outcome. 
Serious adverse events (SAEs) 
 
A serious adverse event is any untoward medical occurrence or affect that at any dose:  
-results in death; 
-is life threatening (at the time of the event); 

 
 
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-requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
-results in persistent or significant disability or incapacity; 
- any other important medical event that may not result in death, be life threatening, or 
require hospitalization, may be considered a serious adverse experience when, based 
upon appropriate medical judgement, the event may jeopardize the subject or may require 
an intervention to prevent one of the outcomes listed above. 
 
The clinical course of each event should be followed until resolution, stabilisation or until it 
has been determined that study treatment or participation is not the cause. SAEs, which are 
still ongoing at the end of the study period, must be followed up to determine the final 
outcome.  
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the accredited 
METC that approved the protocol, within 15 days after the sponsor has first knowledge of the 
serious adverse reactions.  
SAEs that result in death or are life threatening should be reported expedited. The expedited 
reporting will occur not later than 7 days after the responsible investigator has first 
knowledge of the adverse reaction. This is for a preliminary report with another 8 days for 
completion of the report.  
SAEs that are clearly not related to trial participation will not be reported immediately but a 
list will be provided every six months.   
 
A predefined list of SAE’s will be reported every six months instead of individually using the 
CCMO-module ‘toetsingOnline’. SAE’s that will be listed and reported every six months are 
the following: 
 
-  SAE’s related to postoperative complications 
 
-  SAE’s related to the standard adjuvant chemotherapy treatment 
 
-  SAE’s that are classified by the steering group as ‘not related to the trial’ 

 
 
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- SAE’s related to diagnostic laparoscopy at 18 months 
SAE’s will only be recorded and reported if occurring in the following study period: from the 
start of the study until one month after the 18 months diagnostic laparoscopy or, in case a 
subject does not undergo the 18 months diagnostic laparoscopy, until one month after last 
day of adjuvant systemic chemotherapy.  
Suspected unexpected serious adverse reactions (SUSARs) 
Adverse reactions are all untoward and unintended responses to an investigational product. 
 
Unexpected adverse reactions are SUSARs if the following three conditions are met: 
1. the event must be serious (see chapter 9.2 ‘serious adverse events’); 
2. there must be a certain degree of probability that the event is a harmful and an 
undesirable reaction to the product under investigation 
3. the adverse reaction must be unexpected, that is to say, the nature and severity of 
the adverse reaction are not in agreement with the product information as recorded 
in: 
- 
Summary of Product Characteristics (SPC) for an authorised investigational product; 
 
The sponsor will report expedited the following SUSARs through the web portal 
ToetsingOnline to the METC: 
 SUSARs that have arisen in the clinical trial that was assessed by the METC; 
 SUSARs that have arisen in other clinical trials with the same investigational product, and 
that could have consequences for the safety of the subjects involved in the clinical trial 
that was assessed by the METC. 
 
The remaining SUSARs are recorded in an overview list (line-listing) that will be submitted 
once every half year to the METC. This line-listing provides an overview of all SUSARs from 
the study medicine, accompanied by a brief report highlighting the main points of concern.  

 
 
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The expedited reporting of SUSARs through the web portal ToetsingOnline is sufficient as 
notification to the competent authority. The sponsor will report expedited all SUSARs to the 
competent authorities in other Member States, according to the requirements of the Member 
States. The expedited reporting will occur not later than 15 days after the sponsor has first 
knowledge of the adverse reactions. For fatal or life threatening cases the term will be 
maximal 7 days for a preliminary report with another 8 days for completion of the report.  
 
Information on all AEs / SAEs and SUSARs will be recorded in the CRF. Furthermore the 
investigators of the participating centers will report SAEs and SUSARs to the investigator via 
e-mail, fax or telephone (C.E.Klaver@amc.nl, G.D.Musters@amc.nl, and P.J.Tanis@amc.nl, 
Fax; 020-5666569, telephone; 020-5669111) upon occurrence.  
 
9.3 Annual safety report 
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year 
throughout the clinical trial, a safety report to the accredited METC, competent authority, and 
competent authorities of the concerned Member States. 
This safety report consists of: 
 
a list of all suspected (unexpected or expected) serious adverse reactions, along with 
an aggregated summary table of all reported serious adverse reactions, ordered by 
organ system, per study; 
 
a report concerning the safety of the subjects, consisting of a complete safety analysis 
and an evaluation of the balance between the efficacy and the harmfulness of the 
medicine under investigation. 
 

 
 
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9.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist.  
 
9.5 Data Safety Monitoring Board (DSMB) 
A central DSMB consisting of a chairman (medical specialist), a medical and a surgical 
oncologist and a statistician who are not involved in the study will be installed to monitor 
quality and patient safety in this multicentre trial according to the standard operating 
procedures. All relevant data, including a full description of local treatments which have been 
performed in each individual patient, all serious adverse events and patient withdrawal, all 
specified per participating hospital will be made available to the DSMB by the study 
coordinators. The DSMB will review the safety data, report their findings to the principal 
investigator and advise on study continuation after 25, 50 and 100 patients are included. The 
principal investigator will submit these reports to the ethics committee along with all relevant 
data. 
 
In order to monitor the potential risk of the delay in adjuvant systemic chemotherapy in the 
HIPEC group, the development of distant metastases will be closely monitored and continually 
reported to the DSMB. Additional information about nodal status at the time of the primary 
resection will be provided. Cessation of the study is warranted in case of a more than 10% 
higher proportion of distant metastases in the HIPEC group (as compared to the control 
group). This difference is only considered to be related to the delay in systemic chemotherapy 
if the proportion of stage III disease is similar in both groups. This stopping rule will be applied 
at the time of the second and third interim analysis (50 and 100 patients). As for the rest, the 
DSMB will counsel the steering committee on study continuation or cancellation based on 
their expertise.  

 
 
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A monitor will be installed and a monitoring program is being drafted in collaboration with the 
Clinical Research Unit of the Academic Medical Centre. The Monitor will check adherence to 
GCP guidelines; in particular the administration of serious adverse events and drug 
accountability registration. The monitor reports to the steering committee. 
 
The practical implementation of the study will be thoroughly examined by means of 
interviews, evaluation of source documents and assessment of the Trial Master File and the 
Investigator File. The administration of essential documents will be evaluated, assessment 
of patient information, verification of all trial subjects’ informed consent forms, studying 
whether the medical history of the trial subjects is in accordance with the in- and exclusion 
criteria, verification of the exclusion criteria related to the trial subjects’ safety will be evaluated 
for a random 25% of trial subjects.  Also source data, the reporting of SAEs and SUSARs, the 
administration of the accountability of the investigational medical products and studying 
whether and how the trial related procedures are described will be verified for 25% of subjects 
at random.   
 
10. ANALYSES 
 
This section contains the statistical analysis of the primary and secondary clinical outcome 
parameters (subsections 10.1 and 10.2).  
In addition, the planned economic evaluation alongside the clinical trial is described in 
subsection 10.3. In absence of a suitable study protocol format to this end the related data 
sources and procedures of the economic evaluation are also described in this section of the 
protocol to prevent having these pieces of information scattered as loose ends over the 
sections mainly describing the clinical study.  
 

 
 
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10.1 Primary clinical study parameter(s)  
The primary endpoint, peritoneal recurrence-free survival at 18 months, will be compared 
between the two study groups, using Kaplan Meier survival analysis with log rank test and a 
significance level of 0.05. Statistical analyses will be performed using SPSS software for 
Windows version 22. 
 
10.2 Secondary clinical study parameter(s)  
Treatment effects will be expressed as a relative risk with 95% confidence interval. Any 
binary secondary outcome measures (e.g. re-operation rate, death, etc) will be analysed by 
using a Fisher’s exact or Chi-square test with a two-sided significance level of 0.05 on an 
intention to treat basis. Continuous variables will be analysed by independent sample t-test. 
Quality of life data (e.g. EORTC-QLQ-C30 and CR-29) will be graphically represented across 
all time points and analysed using a repeated measures analysis of variance. All analyses 
will be intention to treat, whereby patients will be analysed according to the treatment group 
to which they were randomised regardless of whether they complied with this treatment. A p-
value of <0.05 will be considered statistically significant. Subgroup analyses will employ a 
test of interaction to explore whether there is evidence that the treatment effects differ across 
subgroups. As with all subgroups analyses, these will be interpreted with caution, and will be 
considered hypothesis generating. 
 
10.3 Economic evaluation 
General considerations 
The economic evaluation of adjuvant HIPEC followed by systemic chemotherapy against 
adjuvant systemic chemotherapy alone will be performed from the societal perspective as a 
cost-effectiveness as well as cost-utility analysis. The primary outcomes will be the costs per 
year free of PC and the costs per quality adjusted life year (QALY) respectively. Incremental 
cost-effectiveness and cost-utility ratios will be calculated for these outcomes, along with 

 
 
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95% confidence intervals based on non-parametric bootstrapping to account for sampling 
variation. Explorative subgroup analyses will be done for patients presenting with or without 
perforation and for patients with early (simultaneous / <10 days postoperatively) or delayed 
(5-8 weeks postoperatively) HIPEC. Sensitivity analyses will be performed for the unit costs 
of adjuvant HIPEC and for alternative health valuation algorithms (see below). Results will be 
displayed graphically with cost-effectiveness planes and cost-effectiveness acceptability 
curves for willingness-to-pay values up to €100,000. 
Initially, the time horizon will be 18 months with discounting (against generally accepted 
discount rates) of health effects and costs that occur during the second year. If a difference 
in peritoneal recurrence - clinically or subclinically at diagnostic laparoscopy – emerges, we 
will assess longer term (5 years) consequences in scenario-based disease modelling with 
progression parameters derived from literature and cohort studies. The type of modelling 
(simple decision tree, Markov state-transition model, or event history simulation) that best 
suits data availability, data quality, and decisional context at the time of analysis, will be 
selected and subsequently accounted for in a meeting with representatives of ZonMW, CvZ, 
NZa and patient organization ‘leven met kanker’ prior to its application. 
 
Cost analysis 
The analysis will include the direct and indirect medical and non-medical costs including the 
costs of HIPEC, systemic chemotherapy, inpatient stay, outpatient consultations (surgeon, 
gastroenterologist, oncologist, specialized nurse, dietician), out-of-hospital consultations 
(general practitioner, psychosocial care), home care, institutionalized stay (rehabilitation, 
nursing home, palliative care), informal care, out-of-pocket expenses, and production loss 
from sick leave (among members of the work force). Data on volumes will be gathered from 
case reports forms, hospital information systems and with short patient questionnaires at 
quarterly intervals during follow-up. The iMTA Medical Consumption Questionnaire and iMTA 

 
 
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Productivity Cost Questionnaire, adapted to the current study setting and target population, 
will be used.  
Unit costing of resources will be in accordance with current national CvZ/EURiMTA-
guidelines for costing in health care research. Unit costs of adjuvant HIPEC will be 
substantiated with activity based costing at the micro-level during application of the 
interventions in at least two participating centers. All costs will be expressed in euro with 
base year 2016, after price-indexing of unit costs from different calendar years. 
 
Patient outcome analysis 
Dissemination of cancer to the peritoneum may debilitate a person’s quality of life on top of 
recovering from surgery for the primary cancer. In addition to the already mentioned cancer 
specific EORTC-QLQ-C30 and CR-29 questionnaires, patients will be asked to complete the 
short EQ-5D-5L generic health status questionnaire each quarter in order to gather health 
status profiles over time that can be transposed into QALYs using health utility scoring 
algorithms available from the literature (Dutch: Lamers et al; international: Dolan et al). 
These algorithms reflect preferences in the general population, which were elicited with time 
trade-off elicitation techniques. 
 
Budget impact analysis 
The economic evaluation will be expanded with a value of information analysis to assess the 
remaining uncertainty in decision making and the potential for further research.  
Also, a budget impact analysis (BIA) will be performed linking data on disease 
incidence/prevalence, on inclusion criteria, and on health care expenses per case. Both, 
governmental and health care insurer perspectives will be addressed. The time horizon of 
this BIA will be in accordance with the time horizon of the health economic model (see 

 
 
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above): 5 years. This time horizon is a standard in clinical cancer research and it increases 
the likelihood of being able to derive model parameter estimates from the literature and 
cohort studies for the period beyond the initial observation period of 18 months in the current 
study. 
Unit costing for the BIA will reflect the per case expenses that will actually be transferred 
from insurers to suppliers of health care, and may deviate from the ‘real’ unit costs used in 
the cost-effectiveness and cost-utility analyses.  
The budget impact will be assessed under four different implementation scenarios: full 
(100%) or partial (50%) combined with immediate or gradual (linearly over four years) 
implementation of adjuvant HIPEC.  
 
11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
This study will be conducted according to the principles of the Declaration of Helsinki 
(Fortaleza,October 2013) and in accordance with the Medical Research Involving Human 
Subjects Act (WMO) and other guidelines, regulations and Acts  
 
11.2 Recruitment and consent 
The information offered to the patient or representative contains: 
-a statement that the trial involves research 
-a full explanation of the procedure to be followed 
-a full explanation of the nature, expected duration, and purpose of the study 
-a description of any reasonable foreseeable risks or discomfort to the patient 
-a description of any benefits which may reasonably be expected 
-a statement that patient data will be handled with care and confidentiality 

 
 
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-a statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the patient is otherwise entitled, and that the patient may 
discontinue participation at any time without penalty or loss of benefits, in which case the 
patient will receive standard treatment with the same degree of care 
 
11.3 Objection by minors or incapacitated subjects  
Minors and legally incompetent adults are excluded from the trial. 
 
11.4 Compensation for injury 
The AMC Medical Research BV has insurance, which is in accordance with the legal 
requirements in The Netherlands (Article 7 WMO and the Measure regarding Compulsory 
Insurance for Clinical Research in Humans of June 23, 2003). This insurance provides cover 
for damage to research subjects through injury or death caused by the trial: 
- € 450.000,-- (i.e. four hundred and fifty thousand Euro) for death or injury for each subject 
who participates in the research; 
- € 3.500.000,-- (i.e. three million five hundred thousand Euro) for death or injury for all 
subjects who participate in the research; 
- € 5.000.000,-- (i.e. five million Euro) for the total damage incurred by the organization for all 
damage disclosed by scientific research for the AMC as ‘Sponsor (verrichter)’ in the meaning 
of said Act in each year of insurance coverage. The insurance applies to the damage that 
becomes apparent during the study or within 4 years after. 
The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study. 
For UK participants NHS indemnity will apply. 
11.5 Incentives  
Enrolled patients will not receive any special incentives, compensation or treatment through 
participation in this trial. 

 
 
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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
Every randomised patient will be assigned a three digit study number. Communication 
occurs only with this number. The full name and birth date of the patient will only be recorded 
on the informed consent form.    
 
A study coordinator coordinates the study, monitors patient inclusion and protocol steps, 
data collection, data entry, preparation and performs analyses and will report the data. 
Continuous data monitoring, and data collection on a CRF will guarantee complete and real-
time prospective recording of data. Data will be collected and stored at the AMC in a 
separate, closed room. 
 
12.2 Amendments  
Amendments are changes made to the research after a favourable opinion by the accredited 
METC has been given. All amendments will be notified to the METC that gave a favourable 
opinion.  
 
All substantial amendments will be notified to the METC and to the competent authority. 
Non-substantial amendments will not be notified to the accredited METC and the competent 
authority, but will be recorded and filed by the sponsor.  
 
A ‘substantial amendment’ is defined as an amendment to the terms of the METC 
application, or to the protocol or any other supporting documentation, that is likely to affect to 
a significant degree: 
- the safety or physical or mental integrity of the subjects of the trial; 
- the scientific value of the trial; 
- the conduct or management of the trial; or 
- the quality or safety of any intervention used in the trial. 

 
 
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12.3 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited 
METC once a year. Information will be provided on the date of inclusion of the first subject, 
numbers of subjects included and numbers of subjects that have completed the trial, serious 
adverse events/ serious adverse reactions, other problems, and amendments.  
 
12.4 End of study report 
The sponsor will notify the accredited METC and the competent authority of the end of the 
study within a period of 90 days. The end of the study is defined as the last patient’s last visit.  
 
In case the study is ended prematurely, the sponsor will notify the accredited METC and the 
competent authority within 15 days, including the reasons for the premature termination. 
 Within one year after the end of the study, the investigator/sponsor will submit a final study 
report with the results of the study, including any publications/abstracts of the study, to the 
accredited METC and the Competent Authority.   
 
12.5 Public disclosure and publication policy 
Patients are entitled to public disclosure of the results of the trial on the basis of their 
participation in it. The results of research will be submitted for publication to peer-reviewed 
scientific journals. Agreements with respect to participation in publication will be made before 
the start of the trial. Besides the group of principle investigators and research fellows 
authorship is granted to the local investigator of each centre when at least five patients are 
included in the trial and when substantial contribution to the trial (e.g. full completion of CRF 
or intellectual input) is made. When a participating centre includes more than 17 patients 
(>10%), a second author of the participating centre will be added to the author list. Every 
other people who made substantial contribution to the trial will be added to the collaborator 
list.   

 
 
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Table 1 characteristics of randomised and non-randomised comparative studies. 
 
ip =  intra peritoneal, RCT= randomised controlled trial, CS = non randomised comparitive study, T=temperature of intraperitoneal 
infusion, t= duration of infusion, 5FU =fluorouracil, LV =leucovorin, LE=levamisole, MMC =mitomycine-C, Ox =oxaliplatin, ip 
=intraperitoneal, iv =intravenous, po =oral *=selection based on general patient status and invasiveness of surgery, 
(H)IPEC=(hyperthermic) intraperitoneal chemotherapy, IPC = Intra peritoneal catheter, simultaneously placed with primary tumour 
resection or via a percutaneous approach, with or without a subcutaneous reservoir. 
 
 
author, 
year, 
design 
inclusion criteria 
n 
interval  
after  
resection  
Drug, dosage,  
administration route  
Duration and frequency 
methods of  
ip 
administratio
n 
 
Sugerbaker, 
1985, 
RCT 
colorectal cancer 
N+, T4, 
obstruction, 
perforation, age 
<30 years  
36 
2 months 
ip 5FU 1040mg;  
 
daily for 5 days/ every month;  
12 cycles 
 
IPC 
 
30 
2 months  
iv 5FU 12mg/kg 
daily for 5 days/every month;  
12 cycles 
 
Graf, 
1993 
RCT 
colorectal cancer 
electively 
operated with 
curative intent, 
exclusion of stage 
I 
50 
1 day after  
surgery 
ip 5FU 500mg/m2/day 
 
& iv LV 60mg/m2/day 
 
4 hours / daily for 6 consecutive days 
1 cycle 
IPC 
 
50 
1 day after  
surgery 
ip placebo  
 
4 hours / daily for 6 consecutive days 
1 cycle 
IPC 
Scheithauer, 
1998, 
RCT 
colon cancer 
T3/4 and/or N+ 
117 1-5 weeks 
ip LV 200mg/m2 +  
ip 5FU 350mg/m2  
 
iv LV 200mg/m2& 
iv 5FU 350mg/m2 
day 1 and 3 of each iv cycle 
 
 
daily for 4 consecutive days/ each 4 
weeks, total 6 cycles 
IPC 
 
 
119 1-5 weeks  
po LE 50mg/m2& 
 
 
iv 5FU 450mg/m2  
3 times daily for 3 days/ every 2 
weeks; 
daily for 5days/ 2nd course after 4 
weeks, weekly thereafter 
total 6 cycles 
 
Vaillant,  
1999, 
RCT 
colon cancer 
T3/4 and/or N+ 
133 4-14 days 
ip 5FU 600mg/m2 
 
iv 1gram 5FU  
3 hours / daily for 6 consecutive 
days;  
1 cycle 
Once during surgery 
IPC 
 
134  
no chemotherapy 
 
 
Noura , 
2011, 
CS 
colorectal cancer 
positive  
peritoneal lavage  
31* 
simultaneous with 
primary tumour 
resection 
ip MMC 20mg  
T=37C°; t=1hour 
 
iv 5FU/LV or  
po 5FU derivates (n=23) 
Once during surgery 
 
 
Schedule not specified 
Closed IPEC 
procedure 
 
22 
 
iv 5FU/LV or  
po 5FU derivates (n=19) 
Schedule not specified 
 
Tentes, 
2011, 
CS 
colorectal cancer 
T3/4 
40 
simultaneous with 
primary tumour 
resection 
ip MMC 15mg/m2  
T= 42.5-43C° t=90min 
or Ox 130mg/m2  
T= 42.5-43C° t=60min 
 
 iv 5FU/LV in   
Stage III/IV 
Once during surgery 
 
 
 
 
6 cycles 
Open HIPEC 
procedure 
 
67 
1 day 
ip 5FU 600mg/m2 
 
iv 5FU/LV in  
Stage III/IV) 
23 hours / daily for 5 consecutive 
days;  
1 cycle 
6 cycles 
IPC 
Sammartino, 
2012, 
matched CS 
colon cancer 
T3/4NxM0, 
perforation 
(regardless of 
tumour stage), 
signet cell or 
mucinous tumours 
25 
simultaneous with 
primary tumour 
resection (with 
appendectomy, 
omentectomy, 
resection of the round 
hepatic ligament and 
bilateral ovariectomy) 
ip Ox 460mg/m2 
T=43C° t=30min 
iv 5FU 400mg/m2 + LV 
20mg/m2 
iv 5FU/Ox (n=13) 
Once during surgery 
 
 
 
not specified 
Open HIPEC 
procedure 
 
50 
 
iv 5FU/Ox (n=23) 
not specified 
 

 
 
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Table 2; endpoints in comparative studies. 
 
author 
group 
overall / disease free 
survival 
peritoneal 
recurrence 
rate 
complications 
Treatment 
related mortality 
tolerance 
Sugerbake
r 
1985 
 
median overall 
survival (months) 
 
serious  
complications 
(n) 
 
dose limiting events 
 
ip 5FU 
46.3  
20% 
15 
nr 
mucositis 25%, leucocyte 
suppression 60%, abdominal 
discomfort 
abdominal pain 
 
iv 5FU 
47.5  
91% 
16 
nr 
mucositis 40%, leucocyte 
suppression 20%, abdominal 
discomfort 
abdominal pain 
 
p value  
nsA  
0.003B 
nr 
nr 
nr 
Graf  
1993 
 
 
 
postoperative 
complications 
(n) 
in hospital or 
within 
30days(n) 
tolerance 
 
ip 5FU + iv LV nr 
nr 
11 
0 
nausea 5%, diarrhoea 2%, allergic 
reaction 2%, infusion connected 
pain 
 
ip placebo 
nr 
nr 
15 
0 
nausea 15%, diarrhoea 7% 
allergic reaction 0%, infusion 
connected pain 
 
p value  
nr 
nr 
 
nr 
nr 
Scheithaue
r 
1998 
 
actuarial 4-year 
survival rate 
4-year  
life threatening  
side effects (n) 
treatment 
related  
death (n) 
severe treatment associated side 
effects 
 
ip + iv 5FU/LV  83%  
8%  
0 
0 
13% 
 
iv 5FU + po 
LE 
65%  
21% 
0 
0 
3% 
 
p value  
nr 
0.005C 
nr 
nr 
0.01 
Vaillant   
1999 
 
actuarial 5-year 
survival rate 
4-year  
Postoperative 
complications 
(n) 
Postoperative 
mortality (n) 
 
 
ip 5FU 
74% 
8% 
26 
2 
fair 14.9% 
poor 3.3% 
 
no CT 
68% 
10% 
16 
0 
 
 
p value  
0.30A  
nr 
nr 
nr 
nr 
Noura 
2011 
 
 
actuarial 5-year 
cancer specific 
survival rate 
actuarial 5-
year  
 
IPEC related 
postoperative 
complications 
(n) 
Postoperative 
mortality 
Grade 3 complications related to ip 
lavage 
 
ip MMC +  
(iv 5FU/Ox) 
54.3%  
12%  
Grade III/IV=1 
0 
1 
 
(iv 5FU/Ox) 
9.5%  
59.9%  
Grade III/IV=0  0 
0 
 
p value  
0.0001A  
0.0003A  
Nr 
nr 
nr 
Tentes 
2011  
 
actuarial 3-year 
survival rate 
nr 
Overall 
complications 
(n) 
Hospital 
mortality(n) 
tolerance 
 
HIPEC 
MMC or Ox 
(iv 5FU/LV) 
100%  
nr 
16 
1 
nr 
 
ip 5FU 
(iv 5FU/LV) 
69% 
nr 
22 
9 
nr 
 
p value  
0.011A 
nr 
0.05 
0.009 
nr 
Sammartin
o 
2012  
 
median disease free 
survival (months) 
 
Grade I-IV (n) 
 
HIPEC toxicity Grade II 
 
HIPEC Ox 
(iv 5FU/Ox) 
36.8  
4%  
Grade I/II =3 
Grade III =0 
Grade IV =1 
nr 
1 
 
(iv 5FU/Ox) 
21.9  
22%  
Grade I/II =5 
nr 
0 

 
 
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Grade III =1 
Grade IV =3 
 
p value  
<0.01A 
<0.05B 
 
nr 
nr 
 
nr = not reported, A =Log rank, B =Fisher exact, C =Chi square, 5FU =fluorouracil, LV =leucovorin, LE=levamisole, MMC 
=mitomycine-C, Ox =oxaliplatin, ip =intraperitoneal, iv =intravenous, po =oral  

 
 
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Table 3; characteristics of  cohort studies 
 
author,  
year 
inclusion criteria 
n 
interval after  
resection 
Drug, dosage, 
administration route  
Duration / frequency 
methods of  ip 
administration 
  
Kelsen , 
1994 
colon cancer 
N+; T4 with 
obstruction or 
perforation, or 
resected intra-
abdominal M1 
26 
2-5 days after 
resection 
ip floxuridine 500mg/m2 
ip LV 120 mg/m2  
 
 
po levamisol 50mg  
 
 
iv 5FU bolus 200-450 
mg/m2 dose escalation 
 
iv 5FU 450mg/m2/week  
Twice daily for 3 consecutive 
days/ every2 weeks 
3 cycles 
 
3 times a day for 3 days / every 
2 weeks total 1 year 
 
During 3rd ip cycle, daily for 5 
days 
 
 
Every week, total 1 year 
IPC 
Palermo 
2000 
colon cancer 
T3/4, N+ 
45 
nr 
ip 5FU 20mg/kg 
 
 
Radiotherapy 150cGy  
Daily 60-90 minutes for 5 
consecutive days/every 4 
weeks 
6 cycles 
daily for three weeks/ 2 cycles  
with 1 week interval 
IPC 
Seymour 
2008 
colon cancer 
T4 
47* 
Median 57 
days  
(15-148) 
ip 5FU  400 mg/m2  
ip LV  20 mg/m2  
 
 
iv 5FU/LV 
Separate cohorts with 
frequencies of once per 4, 3, 2 
or 1 week(s) 
total 24 weeks 
 
Once every week, max 24 
weeks. 
IPC 
Chouillard  
2009 
colorectal cancer 
T4, pN2, perforation 
or  obstruction 
(regardless of 
tumour stage); 
positive peritoneal 
lavage 
16 
5-8weeks 
ip MMC 80mg/m2  
: T=42-44C° & t=35-
45min 
 
adjuvant iv treatment 
not mentioned 
once 
laparoscopic 
HIPEC 
procedure 
Lygidakis  
2010 
rectal cancer 
N+, neurovascular 
involvement 
87 
22 days  
ip 5FU, Ox, LV, 
Irinotecan 
T=43C°; t=60min 
 
iv 5FU, Ox, LV, 
Irinotecan 
 
second lavage after 25 days 
and third lavage after 2 years. 
 
 
every month, 4 cycles 
laparoscopic 
HIPEC 
procedure 
 
 
ip =  intra peritoneal, T=temperature of intraperitoneal infusion, t= duration of infusion, 5FU =fluorouracil, LV =leucovorin, MMC 
=mitomycine, Cis = cisplatinum, Ox =oxaliplatin, ip =intraperitoneal, iv =intravenous, po =oral; *=10/12 colorectal cancer histology 
in pharmacokinetic study and 37/44 colorectal cancer histology in frequency-escalation study; IPC =  Intra peritoneal catheter 
 
 
 

 
 
COLOPEC study protocol version 9.3 5-12-2018  
69 of 70 
TABLE 4; endpoints in cohort studies 
 
author 
overall survival 
peritoneal 
disease  
recurrence 
complications 
Treatment 
related mortality 
tolerance 
Kelsen 
1994 
 
nr 
nr 
No increase in postoperative 
morbidity 
1 catheter removed of peritonitis 
0%  
ip: Gr 3+ myelosuppression 2/26 
iv 5FU 300mg: Gr3+ 
myelosuppression 2/7, Gr3+ 
mucositis 4/7 
iv 5FU 400mg: Gr3+ 
myelosuppression 2/3, Gr3+ 
mucositis 2/3 
Palermo 
2000  
median follow-up 
130 months (108-
163) 
5-year DFS 51% 
5-year OS 56% 
5/45 (n=4 
relaparotomy 
because of small 
bowel 
obstruction) 
Gr3 chemical peritonitis 7/45 
patients, no bacterial peritonitis 
Gr3 nausea/vomiting 3/45 
Gr4 nausea/vomiting 1/45 
Gr3 haematologic toxicity 2/45 
Small bowel obstruction 6/45 
0% 
Grade I toxicity =49% 
Grade II toxicity=19% 
Grade III toxicity =15% 
Grade IV toxicity =2% 
Seymour 
2008 
nr 
nr 
failure of intraperitoneal access 
n=10: initial failure 7 (pain n=3; 
leakage n=2; infection n=1; 
bowel perforation n=1) 
secondary failure 3 (leakage 
n=1; blockage n=2) 
reason for stopping ip treatment: 
mostly abdominal pain 
nr 
tolerance per treatment frequency  
ip /4weeks nr 
ip/3weeks 87% 
ip/2weeks 77%  
ip/week 0% 
Chouillard 
2009 
 
median follow-up 
15.5 months 
2/16 colorectal 
cancer patients died 
at end of FU. 3/14 
alive with distant 
metastasis 
peritoneal 
recurrence rate 
0% 
overall n=21 
Major n=4 
Minor n=11 
0% 
Major:  
bone marrow aplasia n=2 
Minor:  
low platelet count n=11, 
leucopenia n=9, fatigue n=8, 
nausea n=7 
Lygidakis 
2010  
1 year OS100% 
2 year peritoneal 
recurrence rate 
3% 
0 
0 
no drug toxicity during hospital 
stay 
nr = not reported, ip = intraperitoneal, iv = intranveneous, DFS = disease-free survival, OS = overall survival 
 

 
 
COLOPEC study protocol version 9.3 5-12-2018  
70 of 70 
 
Appendix 1 
 
Screening 
Visit / 
before 
surgery 
Primary 
colon 
cancer 
resection 
HIPEC 
Surgery 
(DOS) 
14 
days 
p.o. 
 3 -18 
months  
p.o. (any 
visit 
during 
this time 
period) 
18 
months 
p.o. 
18 -60 
months 
p.o. (any 
visit 
during 
this time 
period) 
Informed Consent 
X 
 
 
 
 
 
 
Baseline case record form 
X 
 
 
 
 
 
 
Pre-operative case record form 
X 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
Intervention case record form 
 
X 
X 
 
 
X 
 
Blood testing for hematologic 
toxicity  
 
 
 
X 
 
 
 
Diagnostic laparoscopy 
 
 
 
 
 
X 
 
Peritoneal carcinomatosis 
assessment  
 
 
 
 
X 
X 
X 
CRF corresponding with time 
interval from surgery 
 
 
 
X 
X 
X 
X 
CEA and imaging according to 
local standard follow-up 
regimen (including one CT-scan 
thorax/abdomen at 18 months) 
 
 
 
X 
X 
X 
X 
Quality of Life questionnaires 
(EORTC QLQ-C30, CR29)  
X 
 
 
 
X 
 
X 
iMTA Medical Consumption, 
iMTA Productivity Cost, EQ-5D-
5L questionnaires  
X 
 
 
 
X 
X 
X