Evaluation of PET-MRI in Initial Staging of High Grade Rectal Cancer Patients and in the Follow up of Colorectal Cancer Patients.
Phase: NA
Conditions: Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage IIA Colon Cancer, Stage IIA Rectal Cancer, Stage IIB Colon Cancer, Stage IIB Rectal Cancer, Stage IIC Colon Cancer, Stage IIC Rectal Cancer, Stage IIIA Colon Cancer, Stage IIIA Rectal Cancer, Stage IIIB Colon Cancer, Stage IIIB Rectal Cancer, Stage IIIC Colon Cancer, Stage IIIC Rectal Cancer, Stage IVA Colon Cancer, Stage IVA Rectal Cancer, Stage IVB Colon Cancer, Stage IVB Rectal Cancer
Sponsor: Case Comprehensive Cancer Center

 
 
CASE 8212  V1.3 10/18/2013 
CASE COMPREHENSIVE CANCER CENTER 
__________________________________________________________________ 
 
STUDY NUMBER:  
CASE 8212 
 
STUDY TITLE:  
Evaluation of PET-MRI in initial staging of high grade rectal 
cancer patients and in the follow up of colorectal cancer 
patients. 
  
PRINCIPAL INVESTIGATORS: 
Raj Paspulati MD 
 
Department of Radiology 
 
 
 
 
University Hospitals Case Medical Center 
Case Western Reserve University 
 
 
 
11100 Euclid Avenue  
 
 
 
Cleveland, OH   44106  
 
 
 
(216) 844-1542 
 
CO-PI: 
Smitha Krishnamurthi MD 
Department of 
 
 
University Hospitals Case Medical Center 
Case Western Reserve University 
 
 
 
11100 Euclid Avenue  
 
 
 
Cleveland, OH   44106  
 
 
 
(216) 844-1006 
 
 
Conor Delaney MD PhD 
Department of Surgery  
 
University Hospitals Case Medical Center 
Case Western Reserve University 
 
 
 
11100 Euclid Avenue  
 
 
 
Cleveland, OH   44106  
 
 
 
 
(216) 844-7874 
 
CO- INVESTIGATORS: 
Sasan Partovi MD 
 
 
 
Department of Radiology 
 
 
 
University Hospitals Case Medical Center 
 
 
 
 
 
Case Western Reserve University 
 
 
 
Nghi Nguyen, MD, PhD 
 
Department of Radiology 
 
 
 
University Hospitals Case Medical Center 
 
 
 
 
 
 
 
Andrew Sher, MD 
 
Department of Radiology 
 
 
 
University Hospitals Case Medical Center 
 
 
 
 
 
 
Claudia Martinez-Rios, MD 
 
Department of Radiology 
 
 
 
University Hospitals Case Medical Center 
 
Case Western Reserve University 
 
 
 
 
 
 
Case Western Reserve University 
STATISTICIAN: 
Ronald D. Novak, Ph.D., M.P.H., M.P.A. 

 
 
 
 
 
CASE 8212  V1.3 10/18/2013 
 
2 
 
Department of Radiology 
 
University Hospitals Case Medical Center 
 
Case Western Reserve Radiology 
 
11100 Euclid Avenue 
 
Cleveland, OH 44106 
 
(216) 844-7519 
 
SPONSOR: 
Philips Healthcare 
 
 
CLINICAL FACILITY: 
University Hospitals Case Medical Center  
 
 
 
 
 
APPROVALS: 
Protocol Review and Monitoring Committee: Pending 
 
 
Case Cancer IRB: Pending 
 
 
 
 
 
STUDY COORDINATOR: 
Clinical Trials Unit 
 
University Hospitals Case Medical Center 
 
Case Western Reserve University 
 
11100 Euclid Avenue 
 
Cleveland, OH 44106-5065 
 

 
 
 
 
 
CASE 8212  V1.3 10/18/2013 
 
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TABLE OF CONTENTS 
 
 
 
        
 
 
Contents 
1.0 
BACKGROUND AND RATIONALE ................................................................................ 4 
2.0 
OBJECTIVES ...................................................................................................................... 5 
3.0 
PATIENT/SAMPLE SELECTION...................................................................................... 5 
4.0 
REGISTRATION PROCEDURES ...................................................................................... 6 
5.0 
RESEARCH PLAN ............................................................................................................. 7 
5.1 Study procedures and data analysis plan ............................................................................... 7 
5.2 Risks ...................................................................................................................................... 8 
5.3 Benefits ............................................................................................................................... 10 
5.4 Alternatives to Participation ............................................................................................... 10 
5.5 Data and Safety Monitoring ................................................................................................ 10 
6.0 
STUDY PARAMETERS ................................................................................................... 10 
7.0 
CORRELATIVE STUDIES (if applicable) ....................................................................... 11 
8.0 
STATISTICAL CONSIDERATIONS ............................................................................... 11 
9.0 
RECORDS/DATA TO BE KEPT ..................................................................................... 11 
10.0 REFERENCES .................................................................................................................. 13 
 
 

 
 
 
 
 
CASE 8212  V1.3 10/18/2013 
 
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1.0 
BACKGROUND AND RATIONALE  
 
 
Colorectal cancer is the 2nd leading cause of cancer related deaths in the US(1). Colon 
cancer accounts for 71% and rectal cancer for the remaining 29%(2). Treatment for both entities 
is primarily surgical with a 90% survival at 5 years when diagnosed in a localized stage, 70% for 
regional and 10% for metastatic disease(3). Imaging plays a crucial role in the diagnostic workup 
of these diseases. Both, CT and MR, have their roles in diagnosis and initial staging of both 
colon (CT colonography) and rectal cancer (Pelvic MR). Furthermore they also contribute 
substantially in follow up and restaging, along with PET-CT. 
 
Determining T and N staging of rectal cancer is mainly done with MR given its superior 
tissue resolution over CT and PET-CT(4, 5). In particular for T staging similar accuracy was 
reported when comparing endoscopic ultrasound and MRI in cases of histologically proven rectal 
cancer (4). While T2 weighted sequences give a detailed anatomy and reach of the lesion as well 
as morphologic data regarding lymph nodes of the area, DWI sequences helps evaluate the 
cellular composition of both the tumor and lymph nodes showing as hyperintense lesions those 
with a high cellular component. On the other hand, PET-CT is used mainly in aggressive, or high 
grade, rectal cancer and locally advanced stages because of its high sensitivity depicting 
metastatic disease which might either change the therapeutic approach or suspend unnecessary 
interventions(6, 7). The diagnostic accuracy of PET/CT for M staging is higher than that of CT 
alone.  
 
Follow up in successfully treated patients, both in colon and rectal cancer, contributes to 
increased survival rates, as it has been proven that patients undergoing liver imaging during 
follow up have a 25% lower mortality rate(8). While CT is the image modality of choice, because 
of availability and price, MR is more sensitive for detecting and classifying liver lesions(9) while 
PET-CT is more sensitive in detecting extrahepatic disease(10). 
 
Given the obvious advantages, described above, of both MR and PET-CT in staging, 
follow up and restaging of these diseases, it is our objective to test the performance of PET-MRI 
in these diseases since it is our belief that this hybrid imaging modality will prove superior to 
current single imaging modality options, namely MRI, CT and PET-CT. 
 

 
 
 
 
 
CASE 8212  V1.3 10/18/2013 
 
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2.0 
OBJECTIVES 
 
 
Our objective is to test the diagnostic performance of PET-MRI in two different settings. 
The first setting is the staging of preoperative high-grade rectal cancer patients, defined by T3 
stage or higher or N1 stage or higher or presence of metastasis, that are referred to PET-CT and 
MRI. In this population Pathology will be the gold standard when available for local staging and 
PET/CT for M staging. When Pathology is not available, both MRI and PET/CT results will be 
used to determine T and N stage.  
The second setting is the follow up of colorectal cancer patients that are referred to PET-
CT with or without a diagnostic MRI request by their physicians. In this second group the gold 
standard for recurrence will be obtained from analyzing CEA levels and PET/CT and MRI 
results. Pathology results will be used as well whenever available. 
 
A secondary objective is to test different attenuation correction MR sequences and novel 
diagnostic MR sequences. 
 
3.0 
PATIENT/SAMPLE SELECTION 
 
 
Every patient that is scheduled to get a PET-CT at UH Case Medical Center either for 
preoperative high-grade rectal cancer or for colorectal cancer follow-up will be invited to join 
this pilot study. Initially, 10 patients per group will be invited to participate. We expect to recruit 
this number of patients in a two year period at the most. 
 
Inclusion Criteria: 
- 
Either having a T3 (The cancer has grown through the muscularis propia and into the 
outermost layers of the colon or rectum but not through them) or higher, node positivity 
or metastatic lesion in the context of rectal cancer or being studied for colorectal cancer 
follow up, independent of the renal function 
- 
PET-CT should be requested by a referring physician. In the case of having an MR 
requested as well, it will be reported from the MRI images generated in the PET-MRI 
- 
Stable physical medical conditions to undergo a MRI 

 
 
 
 
 
CASE 8212  V1.3 10/18/2013 
 
6 
- 
Informed consent must be given and signed prior to study enrollment 
- 
Patient should be over 21 years old 
 
Exclusion Criteria 
- 
Refuse to give and/or sign the informed consent 
- 
Subjects who do not meet the above mentioned inclusion criteria 
- 
Subjects who have a pacemaker 
- 
Subjects who have a metallic prostheses either in the pelvis or in the abdomen that will 
interfere with the MR imaging of that anatomical area 
- 
Subjects who suffer from claustrophobia 
- 
Pregnant women 
- 
Cognitive impairment that affects the subjects ability to give consent 
 
4.0 
REGISTRATION PROCEDURES  
 
The potential participant will be informed of the ongoing protocol during the visit to 
his referring physician where he will also be provided the consent form. He/She will then be 
formally invited to participate in this research study at the time of the appointment for the 
diagnostic PET-CT examination. A member of the research team will provide all information 
and answer questions related to the planned study. This study member will also screen the 
potential candidate for the inclusion and exclusion criteria.  The candidate subject will only 
qualify for the participation in the study if meeting all inclusion/exclusion criteria as listed in 
Sections 3.2 and 3.3. The patient will then first be screened for MRI safety using the standard 
MRI informed consent form as typically used for all diagnostic MRI as a standard of care at 
UHCMC. 
If the candidate subject is confirmed to meet the inclusion/exclusion criteria and to 
qualify for safety features for a diagnostic MRI scan and is interested in participating, the 
Informed Consent form will be given to the patient. The patient will have the opportunity to 
discuss the Informed Consent Form with family or friends from the time he/she is consented 
to the time of the examination. 

 
 
 
 
 
CASE 8212  V1.3 10/18/2013 
 
7 
The study team member will then obtain the permission from the patient to 
participate. The member of the research team will go over the informed consent form with 
the candidate subject. 
 
5.0 
RESEARCH PLAN  
 
5.1 Study procedures and data analysis plan 
 
Patients who enroll in this study will receive their clinically requested diagnostic 
PET-CT and a PET-MRI. When a diagnostic MRI is additionally requested, a report will be 
generated from the MRI images obtained in the PET-MRI. Both exams will be performed at 
the Seidman Cancer Center as part of their normal diagnostic care and will meet all of the 
institutionally imposed criteria for these studies. For research purposes, additional MR 
sequences that are completely harmless to the patient, but haven’t yet been FDA approved for 
the clinical arena, will be performed. If any additional relevant information is discovered 
because of these latter sequences proper communication of these findings to the referring 
physician will be done. 
Using the same F18-FDG injection PET-MRI will be performed, before or after the 
clinically requested PET-CT. If an MRI has also been requested, the report will be generated 
from the MRI images performed in the same scanner as the PET-MRI. After completion of 
the first scan, be it the PET-MRI or the PET-CT, the patient will immediately undergo the 
other examination. No additional F18-FDG injection will be required. MR contrast agents 
may be injected if it’s requested by the referring physician and there are no contraindications. 
As a preparation for the MRI examination, all subjects except those with prior rectal surgery 
will receive a small amount of rectal gel to allow enhanced lesion detection. Intramuscular 
glucagon (1 mg) will be administered to all subjects to help relax the bowels during the MRI 
examination, unless there are contraindications to it which include history of glucagon 
hypersensitivity or pheochromocytoma. If the MRI is clinically ordered, the rectal gel and 
glucagon administrations are standard of care. However, they are research if the MRI is not 
ordered by the referring physician. 

 
 
 
 
 
CASE 8212  V1.3 10/18/2013 
 
8 
The patient will be inside the PET-MRI scanner for approximately 60-90 minutes 
whether or not an MRI is performed. 
All the imaging data obtained from the patient will be stored in the Radiology 
Department research PACS after a unique code that links the patient to its identifiers is 
assigned by a CREC-trained certified co-investigator. All the clinically requested exams will 
be archived in the Department of Radiology clinical PACS system. Similarly, the PI’s and 
Co-PI’s reports that are generated from the clinical images obtained will be permanently 
archived in Radiology’s IDX medical record system. If after reviewing the research data, a 
finding not previously seen in the clinical images, becomes apparent appropriate steps will be 
taken to inform the patients referring physician. 
 
5.2 Risks 
 
The risks associated with the PET/MRI scan are the same risks as those posed by 
individual PET and MRI scans. A known risk related to MRI examinations is that the MRI 
magnet could attract certain kinds of metal that may cause injury to the patient. In order to 
avoid that, patients will be screened for any hazardous metal object that they may have or is 
implanted inside their body which includes heart pacemakers, intracranial aneurysm clips, 
heart valve prostheses and other implanted devices that are not compatible with MRI. 
Although there is no risk from ionizing radiation with MRI, subjects will be exposed to 
strong magnetic fields and radiofrequency pulses common to clinically used MRI systems, 
neither of which are associated with any known detrimental health effects. 
Some of the experimental MR sequences that will be performed are not yet approved 
by the FDA for clinical use or have been partially approved for a certain type of surface coil 
in our scanner. These are already being used in a research setting and during clinical workup 
of patients outside the USA(11) without evidence of any adverse events. 
For some types of MRI scans, when clinically indicated and requested by the 
physician, MR contrast agents may be used to enhance the MR images. These contrast agents 
to be used are approved by the FDA, are commercially available, and are used within label 
indications. With these contrast agents there is a risk of an allergic or fibrotic reaction which 

 
 
 
 
 
CASE 8212  V1.3 10/18/2013 
 
9 
occurs more often with x-ray contrast than with MRI contrast agents. Every effort will be 
made to minimize the risk of such reactions in this study by not exposing subjects who have a 
history of kidney disease (GFR >30mg/min), which is the cohort who most frequently 
exhibits fibrotic reactions, to these contrast agents. Generally, an intravenous injection of 10-
20 ml will be used provided that the subject has no known reaction to contrast agents used in 
previous MRI scans. As with all such injections, bleeding, bruising, dizziness, fainting or 
infection may occur. Also, the injection may be painful but the discomfort should be brief 
and efforts will be made to minimize the pain. These risks, however, are part of the patient’s 
clinical care and not a consequence of the research. 
The MRI scanner makes a loud buzzing sound during the exam that could affect a 
patient’s hearing. In order to protect patient from this sound, they will be provided earplugs 
during the exam. There might also be some claustrophobia-related discomfort involved with 
being required to lie still in a small space. If this occurs, patients can signal the technologist 
attending the MRI/PET who will terminate imaging immediately. The subject will be 
removed from the MRI machine and regarded as being withdrawn from the study. In effect, 
the screening process for the MRI portion of PET/MRI imaging will be the same as that done 
with clinical MRI. The risks associated with a PET scan include radiation exposure from the 
radioactive tracer. However, additional injection of a radiopharmaceutical is not required for 
the proposed study since patients will have been injected for their clinical PET scan. Thus, 
participation in this study does not expose subjects to additional ionizing radiation.  
Finally, there is the potential risk of breach of confidentiality. To diminish this risk, 
we will assign each patient a unique study code that will link data to patient identifiers and 
the key will be stored separately. Deidentification will take place while transferring the 
images to the research PACS and will be performed by a CREC-trained certified co-
investigator. The key connecting deidentified data to the patient will be generated at that 
same moment by the same co-investigator and stored in a laptop with an encrypted hard drive 
for three years after completion of the study, after which it will be destroyed. Only the PI and 
the co-investigator in charge of deidentifying patient data will have access to that computer 
that will be kept by the PI in his office. 
 

 
 
 
 
 
CASE 8212  V1.3 10/18/2013 
 
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5.3 Benefits 
 
While there is no direct benefit anticipated for patients in this study, the study may 
lead to advantages for them because of the improved resolution of imaging being offered by 
MRI which would not otherwise, in some cases, be performed. The study also spares patients 
two separate visits for a pelvic MRI, and abdominal CT, when an MRI would otherwise have 
been ordered. 
There may be a benefit for further patient populations in that the investigators create 
knowledge about the performance of the PET-MRI as a one stop exam for these diseases.  
 
5.4 Alternatives to Participation  
 
This study does not involve a change to the standard clinical care of the participant, 
except for additional imaging time. There will be no consequences to individuals who 
withdraw or step down from the study. The subject will not undergo the PET-MRI imaging 
sequences if he/she refuses to take part in the study. Only the clinically indicated diagnostic 
PET-CT and, if requested, MRI will be performed. If a subject withdraws during the 
procedure of the study, the investigators will use the data as acquired up to the point of 
withdrawal. 
 
5.5 Data and Safety Monitoring 
 
Data and safety monitoring of subjects enrolled in the study will be performed by the 
principal investigator (PI) and co-investigators. All of the patients will be informed about the 
minimal risks related to their diagnostic PET-MRI study. 
 
6.0 
STUDY PARAMETERS 
 
The study parameter is the PET-MRI data. The results of the analysis of this data 
(MRI findings, SUV, etc.) will be reported using special spreadsheets designed for this 

 
 
 
 
 
CASE 8212  V1.3 10/18/2013 
 
11 
purpose and will be introduced into an electronic database (REDCAP) using the code given 
to the patient as the only PHI. 
 
7.0 
CORRELATIVE STUDIES (if applicable) 
 
This study is not designed as a correlative study. 
 
8.0 
STATISTICAL CONSIDERATIONS 
The sample size was determined by the number of patients Philips Healthcare® has 
agreed to fund and is acceptable for a pilot study. Continuous variables will be expressed as 
mean ± standard deviation. Comparisons between continuous variables will be performed by 
using the Student t test. Comparisons between qualitative variables will be performed by using 
the χ2 test with the Yates' correction or McNemar’s test as appropriate.  
Sensitivity, specificity, positive and negative predictive values, and accuracy for PET-CT 
and PET-MRI with their 95% confidence interval will be calculated by using the standard 
formulas according to the criterion standard. Concordance between PET-CT and PET-MRI 
techniques will be assessed by using the McNemar test that evaluates whether the discrepancies 
between both techniques are higher than those observed by chance alone. 
All calculations and statistical parameters will be calculated using Systat, Ver. 13.05 
(Systat Software, Chicago, IL) or MedCalc Software, Ver. 12.3 (MedCalc Software bvba, 
Brussels, Belgium).  
 
9.0 
RECORDS/DATA TO BE KEPT 
 
As with all patient images obtained in the Department of Radiology, the PET-MRI 
and PET-CT images that are obtained in this study will be archived in the Department of 
Radiology’s research PACS system. The clinical MRI and PET-CT images will be archived 
in the Department of Radiology clinical PACS system. Similarly, the PI’s and Co-PI’s reports 
that are generated from the clinical images obtained will be permanently archived in 

 
 
 
 
 
CASE 8212  V1.3 10/18/2013 
 
12 
Radiology’s IDX medical record system. Copies of the results tabulated as described in 
Section 5 and 6 will be kept for a period of 3 years after publication or after approval of 
marketing the PET/MRI. 
 

 
 
 
 
 
CASE 8212  V1.3 10/18/2013 
 
13 
10.0 
REFERENCES 
 
1. 
http://www.cdc.org. 
2. 
http://seer.cancer.gov. 
3. 
Haggar FA, Boushey RP. Colorectal cancer epidemiology: incidence, 
mortality, survival, and risk factors. Clinics in colon and rectal surgery. 
2009;22(4):191-7. Epub 2010/11/03. 
4. 
Fernandez-Esparrach G, Ayuso-Colella JR, Sendino O, Pages M, 
Cuatrecasas M, Pellise M, et al. EUS and magnetic resonance imaging in the 
staging of rectal cancer: a prospective and comparative study. Gastrointestinal 
endoscopy. 2011;74(2):347-54. Epub 2011/08/02. 
5. 
Herrmann KA, Paspulati RM, Lauenstein T, Reiser MF. Benefits and 
challenges in bowel MR imaging at 3.0 T. Topics in magnetic resonance imaging : 
TMRI. 2010;21(3):165-75. Epub 2010/06/01. 
6. 
Poeppel TD, Krause BJ, Heusner TA, Boy C, Bockisch A, Antoch G. PET/CT 
for the staging and follow-up of patients with malignancies. European journal of 
radiology. 2009;70(3):382-92. Epub 2009/05/02. 
7. 
Veit-Haibach P, Treyer V, Strobel K, Soyka JD, Husmann L, Schaefer NG, et 
al. Feasibility of integrated CT-liver perfusion in routine FDG-PET/CT. Abdominal 
imaging. 2010;35(5):528-36. Epub 2009/07/14. 
8. 
Desch CE, Benson AB, 3rd, Somerfield MR, Flynn PJ, Krause C, Loprinzi CL, 
et al. Colorectal cancer surveillance: 2005 update of an American Society of Clinical 
Oncology practice guideline. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. 2005;23(33):8512-9. Epub 2005/11/02. 
9. 
Donati OF, Hany TF, Reiner CS, von Schulthess GK, Marincek B, Seifert B, 
et al. Value of retrospective fusion of PET and MR images in detection of hepatic 
metastases: comparison with 18F-FDG PET/CT and Gd-EOB-DTPA-enhanced MRI. 
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 
2010;51(5):692-9. Epub 2010/04/17. 
10. 
Dias AR, Nahas SC, Camargo EE, Nahas CS. Recent evidences of the use 
of 18F-fluorodeoxyglucose positron emission tomography in the management of 
colorectal cancer. Journal of surgical education. 2007;64(2):114-9. Epub 
2007/04/28. 
11. 
Martinez-Moller A, Eiber M, Nekolla SG, Souvatzoglou M, Drzezga A, Ziegler 
S, et al. Workflow and Scan Protocol Considerations for Integrated Whole-Body 
PET/MRI in Oncology. Journal of nuclear medicine : official publication, Society of 
Nuclear Medicine. 2012;53(9):1415-26. Epub 2012/08/11.