Advanced imaging in HIPEC for peritoneal carcinomatosis of colorectal origin; a feasibility study

Peritoneal carcinomatosis (PC) of colorectal origin occurs in 13 per cent of
the patients at time of diagnosis and 25% of the patients develop PC at
recurrence[. Prognosis for PC without aggressive therapy is very poor. Without
treatment, median survival is approximately 3 months. Cytoreductive surgery
(CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has been
reported to have good results on survival of metastasized gastro-intestinal and
gynaecological carcinomas. Median survival of patients with PC of colorectal
origin has improved with 21-30 months with up to 40% 5 year survival.

CRS combined with HIPEC is a procedure that has high rates of morbidity and
mortality. A multi-institutional study was performed of 1.290 (523 with primary
colorectal adenocarcinoma) patients who were treated by open CRS and HIPEC for
non-ovarian malignancies. Overall morbidity and mortality rates were 33.6% and
4,1% respectively. A careful decision has to be made whether it is worth for
patients to undergo an operation with such high rates of morbidity and
mortality.

The peritoneal carcinomatosis index (PCI) is an important tool for predicting
survival and for determining whether complete resection is possible. The
peritoneum is divided into 13 regions. To each region a score of 0 through 3 is
given according to tumour size found. A study showed a difference in survival
between patients with a PCI <15 and =/>15. Significance difference was
observed in both disease-free-survival and overall survival (p=0,0009 and
p=0,013 and respectively) between both groups. It has been demostrated that the
survival after CRS and HIPEC was correlated to the extent of disease and the
completeness of removing all malignant lesions.

Staging the extent of disease has shown to be viable to assess if patients
should undergo such an invasive procedure. The benefits of the oncologic
outcomes have to be weighed against the high rates of morbidity and mortality.
After staging the procedure can only be successful if all malignant lesions
larger than 2 millimetres are resected prior to chemotherapy cleansing. Image
enhanced modalities such as narrow-band imaging, autofluorescent imaging,
photodynamic diagnosis with 5-ALA, near-infrared imaging with ICG and spray-dye
chromoendoscopy with ICB have shown in different medical fields of speciality
to improve lesion detection, especially of smaller, flatter and harder
detectable lesions. Therefore we should investigate these imaging modalities to
improve survival for patients by having a more complete cytoreduction.

Primary Objective:
-Evaluate tumour detection sensitivity and specificity with the following image
enhancement modalities:

1 *narrow-band imaging*, (NBI)
2 *near-infrared indocyanin green imaging*, (ICG)
3 *5-aminolevulinic acid fluorescent imaging*, (5-ALA)
4 *spray-dye chromoendoscopy with Indigo Carmine* (ICB)

The proposed study is a prospective feasibility study to demonstrate which
imaging modality is most suited for detecting peritoneal metastases.
This study will take place at the VU University Medical Center by the
department of gastro-intestinal surgery.
The duration of the study is determined by the time period in which the sample
size can be operated. We perform around 30 HIPEC procedures per year and hope
to include at least 20 patients in that period.

Preoperative procedure
In the outdoor patient clinic all subjects who meet inclusion criteria will be
informed and asked for oral and written informed consent. Patients are
instructed about the procedure, the alternatives and the adverse events. After
being informed by the physician, the patient receives the
patient-information-letter. Any additional questions will be answered by the
physician or the executive investigator. Patients have a minimal time for
reflection and consultation of one week.
Preoperative screening by the department of Anaesthesiology takes place in the
outdoor patient clinic as well.
In the hospital the preoperative care is conducted as stated by the *general
protocol for preoperative care* of the VU Medical Center department of surgery.
Six hours prior to surgery the patients have to be sober and 2 hours before
surgery no more water is allowed as well.
Three hours prior to anaesthesia 5-aminolevulinic acid (5-ALA) is administered
orally. The dose depends on the body weight (20mg/kg). ICG (0,25mg/kg
bodyweight with a maximum of 5mg/kg bodyweight) is intravenously administered
on the ward, 3 hours prior to surgery.

Intraoperative procedure
Patients are placed in the supine position and receive general anaesthesia. The
surgical procedure will be either performed by laparoscopy or laparotomy (open
procedure), depending on the extent of disease and patient history. If the
procedure is started laparoscopically a 12mm-trocar and rigid laparoscope are
placed after a periumbilical incision is made. Two more 5mm-trocars are
introduced to assist the laparoscope. If the procedure is started by
laparotomy, a midline incision is made from xyfoid to the pubic bone.

The peritoneum surrounding the larger peritoneal metastases is inspected
systematically, according to the Peritoneal Carcinomatosis Index (PCI). The
peritoneum is first inspected by conventionalWL. Next the peritoneum is
inspected using the advanced imaging modalities in a computer-generated
rotating different order:
A. Narrow-band imaging (NBI)
B1. Near-infrared imaging with intravenous fluorescent Indocyanin Green
infusion (NIR-ICG)
B2. Photodynamic diagnosis with orally administered 5-ALA (5-ALA)
C. Spray-dye chromoendoscopy with Indigo Carmine Blue (SDCE)
The techniques are used in a computer-generated randomly different order. This
is achieved by use of the online available Sealed Envelope program.

Per imaging modality (WL, , NBI, NIR-ICG, 5-ALA and SDCE) photographs are taken
of possibly malignant lesions. The photographs will be systematically sorted
according to the Peritoneal Carcinomatosis Index (PCI) and per imaging
modality. After the regions of interest have been evaluated with every imaging
modality, biopsies will be taken of each potentially malignant lesion. A
maximum of five biopsies of apparent healthy tissue will be taken for negative
control. Biopsies of healthy peritoneum will be taken within 2cm proximity of a
potentially malignant lesion. By taking biopsies after all the imaging
modalities have been applied, less biopsies are needed and therefore decreases
the risk of bleeding.

NBI can be initiated by changing the settings on the laparoscopic tower. No
invasive extra procedures is needed for this modality. When the peritoneum is
inspected by laparotomy, the NBI laparoscopic camera is used in an open fashion.
For the imaging technique SDCE (technique C), ICB is sprayed onto the
peritoneum to enhance tissue architecture. A sterile catheter is introduced to
spray the ICB onto the peritoneum. After evaluation of the peritoneum with
SDCE, the ICB is rinsed and aspirated.
Patients will receive either intravenous indocyanin green three hours prior to
surgery (NIR-ICG) or 5-aminolevulinic acid (5-ALA) orally three hours prior to
surgery (techniques B1 and B2).
If patients receive ICG three hours prior to surgery, it is intravenously
administered (0,25 mg/kg bodyweight, diluted in sterile water with a maximum
dose of 5mg/kg bodyweight) on the ward. During surgery either the laparoscope
will be set to near-infrared, or an open near-infrared camera system will be
usedfor fluorescent imaging of the ICG
If 5-ALA is chosen, patients will be asked to drink 5-ALA, dissolved in water,
three hours prior to surgery for optimal distribution and optimal fluorescent
imaging. The laparoscope is set correctly for optimal wavelength emission.
Either the laparoscopic system will be used in an open fashion, or an open
camera system will be used.

The peritoneum is inspected by the operating physician (Dr. Tuynman or Dr.
Meijerink). Two independent surgeons/fellows of gastro-intestinal surgery will
review the photographs taken per imaging modality after the procedure in order
to assess interrater variability ..

After the surgical procedure, all photos and biopsies will be sorted according
to the PCI region and image enhancement technique used. The pathologist will
blindly inspect biopsies for malignancy. The results of the pathologic report
will be correlated to the different imaging modalities. For each modality the
next will be checked:
-Is the photograph taken of the potential malignant lesion correlated to a
positive pathologic finding (e.g. malignant tissue found in biopsy)?
-Is the photograph taken of the potential malignant lesion correlated to a
negative pathologic finding (e.g. no malignant tissue found in biopsy)?
-Is the photograph taken of the potential healthy tissue correlated to a
positive pathologic finding (e.g. malignant tissue found in biopsy)?
-Is the photograph taken of the potential healthy tissue correlated to a
negative pathologic finding (e.g. no malignant tissue found in biopsy)?


Not all image enhancement modalities will be used in the first twenty patients.
The patients will be divided into two groups. Half the patients will receive
ICG for near-infrared imaging and the other half will receive 5-ALA for
photodynamic diagnosis. This is due to possible background interference when
ICG and 5-ALA would be used simultaneously. Simultaneous use of ICG and 5-ALA
is also avoided due to possible interaction of these substances. After the
first twenty patients a trend toward which modalities have superior tumour
detection properties should be visible. The imaging modality with the best
tumour detection properties (e.g. increased sensitivity compared to WL and
comparable specificity) is than selected for further investigation. In this
second phase of the study, all regions of the peritoneum, according to the PCI,
will be visualised.

If any of the image enhancement modalities proves to be of no value, the
modality will be eliminated from the study prematurely. This will be determined
by the project leader. This decision will be based upon ease of use, consuming
of operating time, lack of fluorescence/non-fluorescence.

Postoperative procedure
Postoperative care is given as stated by the VU University Medical Center
*general protocol for postoperative care*
Additional postoperative care is necessary for patients who underwent CRS
followed by HIPEC as stated in the *HIPEC protocol*. This includes 2 days of
postoperative monitoring on the I.C.U. or M.C.U.

Added risk
Participation in this trial adds four extra proceedings*:
1) The use of different imaging modalities may increase operating time and time
under narcosis.
2) Possible adverse reaction to ICG, possible decrease in kidney or liver
function
3) Possible adverse reaction to ICB
4) Possible adverse reaction to 5-ALA
5) Extra biopsies of unhealthy and healthy tissue will be taken
6) The absence of knowledge
* Four extra proceedings because patients will receive either ICG or 5-ALA.

Frequency/damage
The chance for damage as a result of this study is estimated at low risk. This
is because we have anticipated for the potential risks by excluding the
patients with enlarged chance for adverse events as a result of ICG, ICB or
5-ALA usage:
2) Patients with kidney and/or liver insufficiency are excluded. Patients with
iodine allergy are excluded.
3) Patients with hypertension, cardiac ischemia and heart function
insufficiency are excluded. Patients with prior hypersensitivity reaction to
ICB are excluded.
4) Patients with acute or chronic porphyria are excluded. Patients with prior
hypersensitivity reaction to 5-ALA or porphyrins are excluded.
Patients receive ICG, ICB or 5-ALA either intraoperatively or during admission.
Patients are closely monitored and if any adverse event occurs, appropriate
measures according to the substance*s SPC can be taken immediately.

Known risks
1) Increased time under narcosis. Extra time under narcosis is estimated at 15
minutes.
- We believe that these 15 minutes on top of the average operating time of 360
minutes will not cause any damage for the patient.
2) In 1/10.000 patients an anaphylactic or urticarial hypersensitivity reaction
can occur as a result of intravenous ICG injection.
- The damage caused by this adverse event is moderate and reversible.
- If an anaphylactic reaction occurs, the anaesthesiologist can anticipate
immediately
3) ICB may cause a transient elevation of blood pressure and reflex bradycardia
if administered intravenously or orally. In patients with an eGFR< 10 mL/min
clearance may be delayed.
- The damage caused by this adverse event is light and immediately reversible.
- Patients with known unstable hypertension, cardiac ischemia and heart
insufficiency are excluded. Patients with an eGFR< 55 mL/min are excluded from
this trial.
4) 5-ALA can cause phototoxic affects to the skin and eyes 24 hours after
administration by direct sunlight.
- The damage caused by this adverse event is moderate and reversible.
- Patients will not be exposed to direct sunlight 24 hours after 5-ALA has been
administered
5) Bleeding can occur as a result of biopsies
- The damage cause by this adverse event is light and reversible.
- Any bleedings can be coagulated by the operating physician.

No additional physical, psychological or social burdening is caused by this
trial for the study subjects.

Synthesis:
We hypothesize that this study will benefit the patients. Better tumour
visualisation will correlate to a prolonged survival. Intravenous ICG has
already been widely used in different fields of surgery and is FDA approved.
Very little adverse events have been reported, especially in low doses.
Only one case has been described in literature on the use of spray-dye indigo
carmine onto the peritoneum. We do not know how much of the dye will diffuse
over the serosa of the peritoneum. After spraying and visualizing the lesion,
the dye is rinsed of the peritoneum and aspirated. We therefore hypothesize
that very little indigo carmine will be taken up in to the bloodstream.
5-ALA causes hypersensitive skin and eyes 24 hours after administration.
Therefore patients are not exposed to direct sunlight directly after
administration of 5-ALA.
During surgery the patients are under constant surveillance of the
anaesthesiologist and its assistants. If an adverse event occurs, such as a
change in blood pressure, change of heart frequency or respiratory failure, the
anaesthesiologist will intervene.
We believe the potential risks of participating in this study are acceptable
and do not weigh up to the benefits.

After structured risk analysis according to NFU standards, we conclude that the
damage possibly caused by this study is light and the chance is low; therefore
negligible risk.