Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02324023 |
| Other study ID # |
H-4-2014-075 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
November 24, 2014 |
| Last updated |
November 28, 2016 |
| Start date |
November 2014 |
| Est. completion date |
November 2016 |
Study information
| Verified date |
November 2016 |
| Source |
Zealand University Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Denmark: Ethics Committee |
| Study type |
Interventional
|
Clinical Trial Summary
Cancer in the colon and rectum represents a global health burden being the most common
cancer of the digestive tract. It is the second most common cancer in Denmark and only about
half of the patients survive this diagnosis. Thorough characterization of the tumour
preoperatively is very important, since it determines if the patient should be treated with
chemotherapy before operation and, in the future, which operation would be most suitable for
the patient.
Research has shown that endoscopic ultrasound (EUS) is superior to a CT-scan, in determining
the local growth of the tumour in rectal cancer. Today, a CT-scan is the image modality of
choice, and is used in all Danish hospitals when it comes to colon cancer. Hopefully, the
investigators can apply EUS in colon cancer patients and thereby alter our diagnostic
approach, towards a quicker and safer way to determine which treatment the investigators
should offer the patient.
With the screening programme for colorectal cancer in Denmark the investigators will find
more and more cases of colorectal cancers, especially in the early stages, before symptoms
begin. These small tumours put doctors in several dilemmas concerning the strategy of
treatment. Even today, the investigators are very reluctant in offering large-scale
operations to elderly and fragile patients who have been diagnosed with cancer in the
rectum. Instead, local endoscopic operations are performed in selected patients. This
approach has not yet been tried in early colonic cancers. However, it might turn out that
local, endoscopic surgery will show to be beneficial for patients with colon cancers and
maybe even decrease morbidity, mortality and the regenerative period after surgery.
The aim of this PhD-project is to investigate the utility of the EUS-method in
characterizing tumours in the colon and in investigating the blood flow in the tumour.
Description:
Introduction Background: Colorectal carcinoma represents a global health burden being the
most common cancer of the digestive tract. The lifetime risk of developing colorectal
carcinoma is 5%, while the overall number of patients currently alive with diagnosed disease
in Denmark is estimated to be 30.000 patients. Approximately 70% of cases involve the colon,
with the remaining 30% involving the anus and rectum. The mortality rate is intimately
related to its high metastatic ability and therefore prognosis strongly depends on the stage
at diagnosis.
Angiogenesis: Angiogenesis plays an important role in tumour growth and its metastatic
potential and it has been attracting a lot of attention in the past years, due to possible
implications in prognosis stratification, as well as in the targeted treatment of advanced
colorectal cancer. Most cancers depend firmly on the development of a new capillary network
to allow nutrition of newly formed tumour cells. These newly developed blood vessels are
usually highly permeable and allow the access of tumour cells in the general circulation,
leading to metastatic progression. Current treatment strategies for patients with advanced
colorectal cancer include a combined regimen of cytotoxic and biologic therapy targeting
angiogenesis. Thus, there is a great interest in finding alternative imaging tests for
assessing the efficacy of antiangiogenic agents earlier in the course of therapy, based on
functional imaging of tumour vascularity. The benefit that is seen in the survival of
patients with advanced disease by treatment with antiangiogenic drugs can maybe translate in
a neoadjuvant setting or an adjuvant setting in patients with stage III cancer or high risk
stage II cancer.
Staging: Tumour is described by the TNM classification of malignant tumours (TNM).
Accurate preoperative staging of colon and rectum cancer is the main factor determining the
treatment modality for patients and can greatly influence the results. Prognostication and
determination of T stage of colon tumours by using computed tomography (CT) scans have been
widely discussed in the literature. Endoscopic ultrasound (EUS) has been suggested the
staging tool of choice for rectal cancer, when comparing to CT, yet colonic cancers remain
to be investigated.
With the Danish National Bowel Cancer Screening Programme, increasing numbers of early
cancers are revealed. During recent years local treatment in patients with rectal carcinoma
in situ T0 or (T1/T2N0M0) cancers has become more and more accepted and has opened new
avenues in treatment of old, comorbid or in other ways, vulnerable patients. As a result of
the screening programme clinicians will naturally be placed in new dilemmas in terms of
treatment choices, radical versus local excision, for early colonic cancers. Important
issues on colonic cancer excisions, are the intramural extent of invasion and the presence
or absence of lymphnode metastasis.
EUS: Endoscopic ultrasound (EUS) is a method consisting of an ultrasound transducer mounted
on the tip of an endoscope. It has evolved to be useful for both imaging and intervention in
the colon and rectum. The investigators chose to use the radial-array endoscope with its
360o view in evaluating colonic cancers, often presenting as circumferential lesions. EUS
ability to depict the layers of the GI wall has proven the method usefull in staging GI
cancers . Imaging of the blood flow in the vessels and evaluation of blood flow velocity and
flow direction can be carried out using Doppler sonography. Further evaluation of tumour
perfusion can also be performed by low-mechanical contrast enhanced endoscopic ultrasound
(CE-EUS). This is a high-resolution technique enabling minimally invasive evaluation of
tumour perfusion.
According to the European Federation Societies in Ultrasound in Medicine and Biology
(EFSUMB) guidelines, contrast enhanced-ultrasound (CE-EUS) can be utilized to assess early
response to biologic therapy in tumours such as metastatic gastrointestinal stromal tumour
(GIST) or renal cell carcinoma or hepatocellular carcinoma. A similar approach has not been
tested yet in CRC patients using CE-EUS.
In this Ph.D. study the investigators have chosen to focus on left sided colonic cancers
only, since they constitute approximately 70% of all colon cancers and, technically, are
easier to reach than transverse tumours or right sided tumours, thereby making the study
more feasible. The investigators have defined left sided colonic cancers as cancers
including the left flexure proximally and until 15 cm from the linea Dentata distally.
Aims To examine if EUS can be used for stage assessment of left sided colon cancers and to
investigate if endoscopic ultrasound perfusion assessment correlates to histopathological
including immunohistochemical parameters of tumour vascular markers.
Project description The Ph.D. study consists of 4 sub-studies.
1. Endoscopic ultrasound for assessment of T-stage and N-stage in left-sided colonic
cancers Hypothesis: EUS is a feasible staging method to accurately determine T-stage
and N-stage in left-sided tumours.
Objectives: To investigate left-sided colonic cancers with EUS especially concerning
the muscular tumour invasion (tunica muscularis) and the detection rate of local lymph
nodes suspicious of malignancy.
Design: A prospective cohort study. Methods: Any patient at Køge/Roskilde and Herlev
Hospital scheduled for surgery and with histologically determined left-sided colonic
cancer will be included in the study and undergo EUS evaluation. Patients will undergo
a CT-scan and will be staged preoperatively according to this scan. Sensitivity and
specificity will be calculated for EUS and pathology specimens, regarding muscular
invasion. It is expected, based on previous publications, that the distribution between
patients with "bad" tumours (= T4 + T3 with > 5 mm muscular invasion) and "good"
tumours (= T1 - T3 with < 5 mm muscular invasion) will be 45% and 55% respectively.
With an 80% power and 5% type 1 error the investigators will include 74 patients in
order to have an expected sensitivity of 90% and a lower boundary of the 95% confidence
interval at 75%. The investigators will perform an interim analysis after inclusion of
35 patients. If the observed sensitivity will be below 80% the study will be terminated
and there will be focus on method development. If the sensitivity will be higher than
80% the study inclusion will continue until inclusion of 74 patients.
Outcome: Outcome measures will be EUS stage compared to histological stage as well as
to CT scan stage.
2. The correlation between endoscopic perfusion assessments with immunohistochemical
parameters in left sided colonic cancer Hypothesis: EUS is a feasible diagnostic
modality to determine the vascular characteristics of left sided colonic cancer.
Objectives: To investigate quantitative and qualitative EUS parameters of left-sided colonic
cancers with contrast enhanced EUS imaging.
Design: A prospective cohort study. Methods: When EUS staging has been performed in the
cohort of study 2, further evaluation of tumour perfusion will be done by low-mechanical
contrast enhanced endoscopic ultrasound (CE-EUS). Power Doppler vascularity index will be
calculated and used as a measure of tumour perfusion. The volume of tumour perfusion has
previously shown a strong correlation with the vascular density. The perfusion of tumour
tissue per cm3 (automated pixel analysis) will be compared with histologically determined
vascular density. The study is explorative and no sample size calculation is possible based
on present literature.
Outcome: Outcome measures will be endoscopic ultrasound perfusion parameters correlated to
histopathological vascular characteristics of left-sided colonic cancers (e.g. micro vessel
density measured by CD31 staining and double-staining techniques).
Risks and side effects:
Complications may occur during EUS but they are rare. These consist of bleeding from the
tumour, since tumour masses may be very vulnerable, when positioning the scope. The bleeding
is self-limited. Perforation of the bowel is extremely rare. Making the EUS staging
procedure and the endoscopic perfusion assessment will, all in all, take about 10-15
minutes. SonoVue® is not nephrotoxic and the incidence of hypersensitivity or severe
allergic events is lower than with current X-ray agents and comparable to that of other
magnetic resonance contrast agents. SonoVue® is approved for clinical use in EU countries
and administration of the contrast agent showed very low incidence of side effects.
Location:
The data collection will take place at Department of Surgery, Endoscopy Units at Herlev
University Hospital and Køge/Roskilde University Hospital. The endoscopies will be performed
primarily at Herlev Hospital but also at Køge Hospital if necessary EUS equipment can be
provided. If not patients from Køge and Roskilde Hospital will be examined at Herlev
Hospital. The histopathological analyses follow the standard protocols for colorectal
carcinomas routinely performed in the Departments of Pathology at Herlev University Hospital
and Roskilde University Hospital.
Dissemination of the results:
All results, both positive, negative and inconclusive will be presented on national and
international conferences. The results will be submitted for publication to peer-reviewed
journals with Marie Louise Malmstrøm as the first author.
Sponsors:
The research project is initiated by the principal supervisor, Peter Vilmann, MD, DMSc. The
costs associated with the project will be supported from the principal supervisor's
department budget and external funding. The EUS equipment is already available at the
endoscopy department of Herlev and funding for equipment for Køge/Roskilde Hospital have
been applied for at the Research Council of the Region of Zealand. Funding for salary for
the clinical investigator has been applied at private funds and public funds.
Ethics:
The study is ethically approved (H-4-2014-075) and approved at datatilsynet. The studies
performed are registered in www.clinicaltrials.gov as requested by ICMJE (International
Committee of Medical Journal Editors). Research subjects will have to give informed consent,
based on written and oral information before inclusion in the study. Participants will be
informed about any side-effects, risks or unplanned events that might occur during the
implementation of the study. The minimal risks will be outweighed by the potential
implications for future patient care. The study will be carried out with respect to the
mental and physical integrity of the participants.
Guidelines in obtaining informed consent from participants:
Well informed signed consent from the research subjects is an essential criterion for
inclusion in the trial. Both written and oral information will be provided to each candidate
to the study by either the chief investigator or other health care persons that are
qualified in explaining the project in detail. The patient will be made aware of the
possibility of a second person (e.g. caregiver, relative) to be present at the interview.
The interview will take place in a private room in order to provide an uninterrupted
communication. At the interview the detailed information on the project will be covered, in
oral and written form, including an easy-to-read presentation of the project with its
predictable risks and side-effects, expected outcomes and benefits for the research.
The subjects will be entitled to some reflection time before giving consent (24-48 hours),
taking care that the time limit stipulated for complete pretherapeutic evaluation of the
cancer patient is not exceeded, and taking care that the project will not interfere with the
routine clinical investigations and treatments of the patient.
