Rectal Cancer Clinical Trial
Official title:
Preoperative Assessment of Mesorectal Lymph Nodes by Dual Energy CT. PUMK-DECT
Endpoints subproject 1: To develop a reproducible method for the detection of lymph nodes by DECT in operation specimens from rectal resection for cancer. sub project 2: Primary endpoint: To evaluate the sensitivity and specificity for malignant lymph nodes in vitro RC specimens compared with histopathology. Secondary endpoint: To assess DECT as imaging tool for the diagnosis of malignant lymph nodes at RC. Histopathology will be used as reference.Subproject 3: Primary endpoint: To compare the sensitivity, specificity, positive- and negative predictive values, accuracy of DECT and standard MRI. Secondary: To evaluate the value of the gold standard for the use of imaging methods for the description of the lymph node, validated by histopathology. Secondary: to determine the value of tumor diagnostics using DECT.subproject 4: To assess the value of DECT as imaging tool for diagnosing response to chemo radiotherapy of malignant lymph nodes.
Background Long-term survival for patients with cancer of the rectum (RC) is through the
last 20 years dramatically improved from about 30% to 65% . Overall focus on disease with
the creation of multidisciplinary teams, national quality databases certification of
surgeons, etc. have contributed to the development especially in the last 10-15 years . The
introduction of pre-operative Oncology, known as neoadjuvant treatment increased the
survival rate by up to 10% in certain patient series. However, the prognosis remains poor
for advanced cases, qua risk of metastasis and local cancer relapse.
Surgical treatment remains the cornerstone of curative treatment of RC. Total mesorectal
excision (TME) includes resection of both the tumor and the surrounding mesorectal fat. TME
is currently used as the gold standard for surgical treatment of RC. The use of TME has
reduced local relapse rate to less than 10%.
TME surgery combined with preoperative chemotherapy and radiation therapy if the cancer is
in an advanced stage (T3), and often with high-dose radiotherapy and chemotherapy in the
most advanced cases of T-stage 4.
Complications of TME are present in more than 40% of patients. Most often in the form of
wound dehiscence, infection, sexual dysfunction, bowel disorders and the necessity of a
stoma. More than 50% of patients have permanently reduced quality of life.
Minimally invasive therapies (trans-anal endoscopic microsurgery (TEM)) for the curative
treatment of early rectal cancers, is well-validated. The complication rate is low, and
above all, the operative mortality of less than 1% even in the elderly and patients with
comorbidities, opposed to 10% at standard surgery. The use of TEM surgery early in the
rectum cancers in selected patients will thus be able to reduce the risk of complications
and improve the overall long-term survival. Even though the disease-specific survival is
reduced due to a less radical procedure. The Danish screening program for colorectal cancer
will result in a significant increase in the detection of early cancers.
Thus, over the past 10-15 years, there is developed a complex treatment algorithm with
tailored surgery, in combination with oncological treatment if necessary. The full benefits
of the available treatment options require that you pre-treatment, stage classify the
disease so the patient can be allocated to the proper treatment. The tumor extent of
ingrowth into the different layers in the rectum (T-stage) can now be carried out with great
certainty preoperatively.
Patients with tumor stage T1 may be candidates for TEM surgery because only 10% of these
patients have metastases to the lymph nodes. Cancers of the stage T2 may be candidates for
TEM if they have increased operative mortality risk. A local resection of the cancer is of
course undesirable, in the lymph node metastases as they are not included in the resection.
Distant metastases can with certainty be detected with CT and MRI scans. Preoperative
assessment of lymph node involvement is difficult and uncertain for daring to use it to
allocate candidates for local resection.
The indication for TEM treatment of rectal cancers can potentially be extended if you could
allocate patients independent of tumor stage - based on lymph node stage.
The detection of disease spread to the lymph nodes has a decisive impact on the choice of
treatment modality. Moreover the impact on prognosis and local recurrence.
1. Local resection performed only for N0.
2. The number of involved lymph nodes has a prognostic value for the outcome of surgery
for RC.
3. Detection of tumor cells in the lymph nodes at the mesorectal fascia (which forms
circumferential resection margin CRM) increases the risk of recurrence. Patients must
have neoadjuvant oncological treatment.
4. Lymph nodes located outside the mesorectal fascia may require extended lymphadenectomy,
to achieve a good oncological outcome and avoid relapse.
Today, magnetic resonance scan (MRI) and trans rectal ultrasound (TRUS) is used as the gold
standard in the imaging staging of RC. Studies have demonstrated high specificity for the
assessment of T stage and CRM using the preoperative MRI. Comparative high specificity is
obtained in the intermediate hands with TRUS.
In contrast to T stage and CRM classification, the MR and TRUS have shown poor results
compared to N-staging of RC. Even worse results arise for the use of conventional Computed
Tomography Scan (CT) for lymph node diagnostics, with a median sensitivity of 80% (from 62.5
to 91.9%) and median specificity of 77.8% (50- 87.9%).
Research should be directed towards improvement of lymph node diagnostics by RC, in order to
take full advantage of the differentiated treatments.
Dual Energy Computed Tomography (DECT) is an imaging modality, which in recent years has
gained a foothold in the diagnosis of several types of micro-lesions. DECT provides
information on a tissue reaction when it is affected by different energy levels. This gives
you information about its composition, based on the known K-edge value of different
substances. K-edge is defined by the maximum visual attenuation of a substance in a DECT
scan when it is affected by a certain amount of energy. The energy required to achieve a
given k-edge depends on the individual substances atomic size, and therefore increases with
the atomic mass.
The technique is known from, for example, kidney stones diagnosis, pancreatic cancer
staging, vascular anomalies such as classification of aortic aneurysms, detection of
coronary plaques etc.
A study from 2013 by Zalai Pan et al investigated the association between histologically
confirmed gastric cancer, and the discovery of metastatic lymph nodes by DECT. Ninety-six
patients were included. Two groups of radiologists were blinded to the endoscopic and
histological findings. Lymph nodes of 6 mm were included in the N-staging. They found a
sensitivity of 85.4% for N0, 84.4% N1, 91.7% N2. Furthermore, it showed a significant
difference in the uptake of iodine (from the iodine-containing contrast) with the K-edge
value of 33.20 keV, in malignant and non-malignant lymph nodes.
Thus, there is the hope of both iodine and Gadolinium found in X-ray contrast agent, is
absorbed in cancer tissues, and gives a recognizable signal in dual energy CT scanning.
. Hypotheses
1. It is possible to develop a standardized method for DECT scanning of the rectum
specimens, removed during surgery.
2. Metastatic lymph nodes suspected by DECT can be verified histopathological.
3. DECT can increase the sensitivity and specificity of the diagnosis of lymph node
compared to other imaging modalities.
4. The effect of chemo-radiotherapy to the lymph nodes can be detected by DECT
Study Design The study is a prospective observational study, based on patients with newly
diagnosed rectum cancer at the Surgical Department A, Odense University Hospital.
Patients will automatically be divided into 3 groups according to the preoperative
stratification, in a group which will refer to the direct operation either TEM (group 1) or
TME (GROUP2) after the preoperative imaging staging, and a group of 3 which will undergo two
imaging phases, before and after the radio or chemo-radiotherapy before surgery.
Methods Subproject 1: In Vitro DECT scan of rectal specimens. Subproject 1 scan without
contrast
Part 1 procedure: 3 patients with visible lymph nodes in the perirectal fat tissue by MRI
are selected.
Scenario 1 - after TME the specimens will be transported to the pathological institute for
the preparation of 3mm. thick sections from the distal to the proximal resection rim.
- The product is placed in an aluminum lattice.
- All cuts of 3 mm gets numbered and photographed.
- The ex-vivo specimen scan is done; this is done in three different ways to determine
the ideal technique.
1. specimen is scanned between 2 gel plates
2. specimens is scanned in the air
3. specimens is scanned in flooded container
- All sections of 3 mm which is photographed and numbered, gets coupled with its
DECT-scan image.
- The specimens are placed in formalin, and the same scans will be made 24 hours later.
This is to compare the effect of formalin on the DECT scans of specimens.
- The ideal technique for the in vitro DECT scan of specimens will be determined.
The scan with contrast
Second part procedure: Nine patients with visible lymph nodes in the perirectal fat tissue
by MRI will be selected.
- At the preparing meeting with the patients in KA (surgical day center, Svendborg), the
patients will receive information about the study, provided written material, and
consent will be obtained.
- questions in time from the information in KA, to participation in the study to time of
surgery, may be directed to the investigator. The investigator is present at the time
of surgery, and can take questions from the patient.
- Upon written consent from the patients the following procedure will be completed:
1. 5 min. before the default central ligating of a. mesenteric inf. three patients
will receive iv, iodine-containing contrast media, Omnipaque 350 mg iodine / ml, a
total of 10 ml.
For 3pt: intra venous Gadovist (Gadobutrol) 1.0 mmol / ml total 0.1 mmol / kg For 3pt: using
rectoscope and a needle 5 ml of 1 mmol / ml Gadovist will be administered, for examination
of the sentinel node.
2. After TME the specimens are prepared and DECT scanned according to the ideal technique
found by part-1 procedure.
3. All lymph nodes, designated normal or pathological by DECT scan will be analyzed by a
pathologist, who is blinded to the scan results. The lymph nodes will be assessed under the
gold standard for pathological assessment of these (38). In this process it is possible to
remove the lymph node for histopathological validation, as they are numbered according to
photograph and scan images.
4. Pathologist fills in Annex 2 5. Investigator assesses DECT scan pictures, together with
the radiologist. 6. Investigator fills in Annex 1
Subproject 2: assess the sensitivity and specificity of benign / malignant differentiation
in DECT scanning of in Vitro rectal specimens.
- All included patients under the standardized preoperative imaging staging, by written
consent, will get an additional DECT scan of the pelvis, either with Gadovist 1.0 mmol
/ ml, 0.1 mg / kg iv, or after administration of standard CT contrast Omnipaque. DECT
scans can be performed in the same scanner and at the same session as the conventional
CT of the thorax and abdomen. Images should result in ongoing 3mm thick sections of the
pelvis, perpendicular to the rectum wall, from the anorectal transition to promontory
level.
- Conventional CT scan of the thorax and abdomen, and MRI of the rectum will be used as
usual, for the stratification of patients to appropriate treatment cf. Figure 1
- Endoscopist informs about the study and provides written material for signature when
the detection of a rectal cancer is made.
- Questions from patients about participation in the study during the period between
endoscopy and scanning can be directed to the investigator. The investigator is present
at the time of the planned preoperative imaging staging, and accept any questions from
the patient.
- Written acceptance delivered to the investigator in the preoperative imaging staging. A
Copy of the acceptance will be provided the radiologist.
- Item 2-6 from subproject 1 second procedural element is repeated.
Subproject 3: Best protocol during subproject 2, compared with standard MRI of malignant
lymph nodes in the mesorectum in patients who have not received neoadjuvant therapy.
- As mentioned above, the aim is the inclusion of a total of 100 pts. With RC. After the
1-year inclusion period analyzed the scanning images. All the preoperative in vivo
images is reviewed by dedicated radiologists, with a particular focus on lymph node
detection. Morphological criterions as used in MRI is used to determine whether a lymph
node is malignant or not (39), both in the preoperative MR and DECT scanning.
- Radiologists are blinded to the results of the preoperative MRI staging and the
histopathological results.
- Only patients who did not receive neoadjuvant therapy will be included in the
subproject 3, radiologist fills in Annex 1.
- Investigator compares in vivo scan results.
- Investigator compares in vivo scanning results with in vitro scan results and pathology
results. The results are calculated as N0, N1 or N2
Subproject 4: Evaluate DECT ability to follow changes in lymph node status of malignancy
after adjuvant chemo-radiotherapy.
- Patients who have received adjuvant chemo-radiotherapy will be included.
- Following the same procedure as subproject 2 the patients are scanned a second time
after adjuvant chemo-radiotherapy.
- The rescans are described according to the description procedure in subproject 3.
- Annex 1 is filled in.
- Annex 1 from before and after adjuvant radio chemotherapy will be compared.
Statistics and data analysis
Prerequisites for patient collection, for in Vitro DECT scanning after the administration of
Gadovist as a contrast agent:
Median figures for the diagnosis of lymph nodes on MRI in patients with RC are as follows:
- 70% of patients with RC have no visible lymph nodes.
- 15% of patients with RC have visibly benign lymph nodes.
- 15% of patients with RC have visibly malignant lymph nodes (40). 5 shows an in average
5 lymph nodes are seen per patient.
A sample size analysis showed that a number of visible nodes 150 in total were needed to
achieve a sensitivity of 70% (95% CI 56% -80%). Knowing that 5 Iymph nodes are seen in
average per patient would necessitate a population of 100 pts. Included. (15% of 100) x5
Iymph nodes= 75 visible benign Iymph nodes + (15% of 100) x5 Iymph nodes = 75 visible
malignant lymph nodes.
Total number of Iymph nodes = 150
Ethical considerations The project must is approved by the research ethics committees in the
Region of Southern Denmark and by the Data Inspectorate in Odense university hospital
/Svendborg.
First contact with the patient before inclusion in the project will take place on the day
when, after having endoscopic examination, found a malignant tumor in the rectum. The
patient will then be informed about the project by one of the doctors of the department, in
an uninterrupted interview rooms designed for the information of patients and their
relatives. Written information will be disclosed.
Patients will have a minimum of 3 days of reflection before accepting participation in the
project.
When the patient accepts the participation in the project it will only be medically relevant
information that will be obtained in the patient's chart. This will include age, gender,
pregnancy, other diseases, allergies and information on details of the patient's cancer.
DECT scan is a painless procedure that can be done in line with the preoperative scans.
Disregarding the known risks of administering the contrast agent in the form of anaphylactic
reactions, patients are not exposed to medical risk. Using gadolinum based contrast agents
are suspected to be contributing to nephrogenic systemic fibrosis (NSF), but there is no
case of this by the recent report of Committee for Medicinal Products for Human Use (CHMP)
in 2007. Allergic reactions to iodinated contrast agents are described with a frequency of
0.2%, most commonly in the form of hives. Serious adverse reactions, as anaphylactic shock
is described with a frequency of 0.01%.
Patients in sub-project 1 are under the administration of contrast agent preoperatively
under close surveillance by the anesthesiologists, and any possible allergic reaction could
be treated immediately.
Included patients will be exposed to increased radiological radiation, equivalent to 1-10
mSv and therefore only one additional CT scan of the abdomen.
The selected specimens will be treated in exactly the same way as it is legally described in
that matter. The investigator will, in the usual pathological preparation of the specimens,
photograph the specimens and categorize them in the project gradient time. After completing
the project, the picture material will be made anonymous.
It should be emphasized that the results of the experiments related to the scans will not to
have a therapeutic impact.
Perspective In the event that the study shows that DECT enhances the quality of the imaging
staging of patients with RC, the consequences will be substantial. If the accuracy of lymph
node positive for RC reaches 90%, a local resection would be possible for the 10% of the
lymph nodes positive T1 tumors. Furthermore you may be able to offer local resection for the
75% of T2 and T3 early cancers that have not spread, and who otherwise meet the criterions
for local resection. With secure node diagnostics, the surgical oncological treatment will
improve in terms of prognosis and the rate of local relapse. Furthermore, one with better
lymph node diagnostics one can avoid unnecessary neoadjuvant chemo-radiotherapy to the
previous false-positive patients. They are between 25 and 50%.
Medical oncology one will be able to assess the effect of chemotherapy on RC patients, with
the possibility of optimizing the oncological treatment.
Opportunities for practical implementation: We have access to dual-CT and contrast. The
feasibility study is completed.
Study design problems:
There is a risk of categorizing some of the lymph nodes seen on the preoperative DECT scan
as false positive, if they are not found in the in-vitro scans, due to the effect of
radiation therapy. However this is a fact for both MRI and DECT.
;
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