PET and PET/CT in Clinical Trials

PET and PET/CT in Clinical Trials Nathan C. Hall, M.D., Ph.D. The Ohio State University Medical Center CALGB Imaging Core Lab CALGB Imaging Committee Outline Introduction to PET Positron Emitter Physics Instrumentation Radiopharmaceuticals Clinical considerations Patient Preparation 1

Outline Evaluation of PET scans Normal Uptake Quantification Issues relevant to centralized data collection and evaluation Roles of the imaging core lab QA What is PET? Positron Emission Tomography 2

Definition Positron Radionuclide imaging using unconventional positron emitting radiopharmaceuticals Emission Detection of radiation energy emitted from the patient rather than transmitted through the patient Tomography Computer generated 3 dimensional images of the radionuclidic distribution within the patient Radiography x - rays 3

Conventional Nuclear Imaging γ - rays What Makes PET different conventional Nuclear Medicine? Positron emitter physics B+ annihilation resulting in two 511KeV photons emitted in opposite directions Instrumentation differences though image reconstruction techniques similar Short lived radionuclides requiring on site production (cyclotron) 4

What Makes PET different than SPECT? Positron emitter physics B+ annihilation resulting in two 511KeV photons emitted in opposite directions Instrumentation differences though image reconstruction techniques similar Short lived radionuclides requiring on site production (cyclotron) Nucleus Positron Annihilation Emitted Positron Diametrically opposed 511 kev photons Positron-electron annihilation 5

What Makes PET different than SPECT? Positron emitter physics B+ annihilation resulting in two 511KeV photons emitted in opposite directions Instrumentation differences though image reconstruction techniques similar Short lived radionuclides requiring on site production (cyclotron) Positron Emission Tomography Dedicated PET Scanner with 360 degree ring of detectors 8-16-24 rings FOV 6

Computed Tomography PET Possible LOR s from one detector Technical developments Attenuation correction 7

What Makes PET different than SPECT? Positron emitter physics B+ annihilation resulting in two 511KeV photons emitted in opposite directions Instrumentation differences though image reconstruction techniques similar Short lived radionuclides requiring on site production (cyclotron) Cyclotron -production of proton rich radionuclides - O-18 (p,n) F-18 8

Common Positron Emitters TABLE 1: Commonly Used PET Radionuclides Nuclide Half-life 11 C 20.3 min 13 N 9.97 min 15 O 124 sec 18 F 110 min 68 Ga 68 min 82 Rb 67 sec Common PET Radiopharmaceuticals Oxygen Ammonia Water Acetate Fluoride Ion Carbon Dioxide Fluorodeoxyglucose 9

18F-Fluorodeoxyglucose (FDG) HO HO HO HO HO HO 18 F O OH OH OH Glucose FDG Excellent metabolic imaging agent FDG Metabolic Pathway Fructose- 6- Phosphate hexokinase H 2 O CO 2 FDG uptake is proportional to glycolysis 10

Clinical Considerations Patient preparation Fast 4-6 hours Low carbohydrate/ high protein diet 24 hours prior Special preparation for diabetics Light breakfast, normal morning insulin Skip lunch Scan early afternoon No insulin two hours prior to FDG injection Plasma glucose < 180 mg/dl 11

Patient preparation Reducing physiologic uptake Caffeine decreases cardiac uptake by fatty acid metabolism Benzodiazepines may reduce muscular and brown fat uptake Diuretics reduce urinary tract activity Bowel cleansing reduces gastrointestinal tract activity Atropine may reduce secretions in H&N patients Patient preparation Other tips No talking during uptake (particularly head and neck cases) No heavy exercise day before Upright or semi-upright position reduces genioglossus muscle activity 12

Patient preparation FDG injected Patient rests 1-2 hours (timing key for trials) Scan (15-30 minutes) Other guidelines Post surgery 2 months Post radiation 6 months (at least 2 months) Post chemo cycle 2 weeks or just before next Post chemo course 2 months This is where we are pushing the envelope in clinical trials. 13

PET Scan Evaluation Normal uptake and variants 14

Normal uptake and variants Normal uptake and variants 15

Normal uptake and variants Normal uptake and variants 16

Normal uptake and variants Quantitative PET 17

Equation SUV (activity * body weight) / dose Factors affecting SUV Plasma glucose Time after injection Scanner resolution Image reconstruction Size of focus PET/CT or CT/PET 18

PET/CT 1+1=3 Precise localization Faster read time Faster acquisition time Patient convenience No outside films! PET/CT 19

PET/CT PET/CT 20

PET/CT Normal uptake and variants 21

Scanning Guidelines for Clinical Trials Calibrate dose and measure residual Scan with arms up Scan consistently head to toe or reverse Scan on same scanner for follow-up studies Scan at same time after injection for followup studies Data submission guidelines FTP or Mail DICOM format Timely submission 22

Core Lab Issues Sites do not scan clinically at same time as protocol Don t know when patients are enrolled Don t have appropriate contact people at sites Tech don t know pt is research protocol when scheduled and scanned. Key Roles of the ICL for Imaging Endpoints in Clinical Trials Train sites for proper data collection Track data collection from sites Ensure that data is collected per protocol Archive data Provide resources for central review of imaging data 23

Key Roles of the ICL for Imaging Endpoints in Clinical Trials Train sites for proper data collection Educate on how to effectively schedule pt for scan at site to be sure scan is acquired appropriately Identification of key imaging personnel at site Webex virtual site visits Site and instrumentation specific site manuals Key Roles of the ICL for Imaging Endpoints in Clinical Trials Track data collection from sites Protocol specific email addresses Notification from CALGB central office of patient accrural Tracking of patients from registration on Email reminders to sites regarding data sets to be submitted 24

Key Roles of the ICL for Imaging Endpoints in Clinical Trials Ensure that data is collected per protocol Insure proper de-identification Review and enter ADF data into database Review data set quality Timing of scan with respect to therapy Scan direction Blood glucose levels Time from injection to scan, etc. Review scan quality Physician visual review Key Roles of the ICL for Imaging Endpoints in Clinical Trials Archive data Place de-identified data onto servers Backup data 25

Key Roles of the ICL for Imaging Endpoints in Clinical Trials Provide resources for central review of imaging data Assist in training of physicians to evaluate imaging data per protocol specifications Provide resources to ensure that physicians have the tools to read studies consistently Collect data from independent reviewers CALGB50303/80302 Setup and Workflows Sites FTP Email PET/CT ADF + DICOM Deidentification and Storage Data Submission to CoreLab Problem? Imaging Core Lab Help Phone Endpoint Data Analysis Mail WebEx DICOM Quality Check Quality Check Report Data Archiving Case receipt Confirmation to Sites Protocol Compliance Check Corelab Database backup Corelab Database Update Physician Review Problems need decision by CALGB Committee? OSU Imaging Core Lab Report QC issues to Committee Send Committee Decision to Sites 26

Imaging Data Archiving & Storage 1 ICL Servers Trials under Server Subjects under Trial 2 3 Studies under Subject Components under Study PET/CT Imaging Data 4 5 6 Auto Excel Tracking QA & QC Following items must be ready in advance: DICOM PET/CT Notification Letters from CALGB Adjunctive Data Form 27

Notification Letters (1): Patient Registration (MUST) Notification Letters (2): Treatment (Optional) 28

Adjunctive Data Form example (MUST) Some form items CRAs can fill out some they can t Identify key imaging contacts at sites and educate them on filling out forms Webex site visits Institution and instrumentation specific site manuals Adjunctive Data Form example (MUST) CRA NM Tech 29

Adjunctive Data Form example (MUST) NM Tech OSU ICL Semi-automated QA Workflow Manual Input: Info is from ADF & Notification Letter Follow-up vs Baseline Timing Consistency Check Automated DICOM Quality Check Image Review by Physician /Radiologist Excel tracking & PDF QC output 30

Major violations: 1. Emission Timing out of protocol maximum range 50-70 minutes post injection; 15 2. Interval between emission and injection out of +-10 minutes for followups compared to baseline; 15 3. Imaging data with format other than DICOM such as jpeg, bmp or films were received 15 4. Incomplete data set. PET missing or CT missing or a few slices missing. 10 5. Scanner changed between baseline and followups. 15 6. Forms must be filled out properly (both CALGB form and ADF) and in a timely manner. 10 [these are forms that go to the ICL, so the ICL would determine if they are filled out correctly.] 7. Blood glucose out of range. 10 8. FDG out of protocol range [8-20mCi] (should the dose be consistent between baseline and followups? E.g., baseline: 300MBq; PC2: 500MBq) 9. Patient fasting less than protocol required 4 hours prior to FDG injection 10. Timing of studies out of protocol range (B01<=30 days prior to start of therapy; PC2 17-21 days after cycle 2 therapy; PC6 6-8 weeks after the last dose) 11. Image Size/Image Resolution/Slice Thickness are not uniform between baseline and followups Minor violations: 1. Data not submitted in a timely manner (need to define and?add to protocol?) 3 Sites having PET/CT exams in other local institutions sometimes take a long time (or fail) to get the data set and submit to ICL. Sometimes site wants ICL to contact those institutions for the data submission. This should be the responsibility of the participating site 2. Data sets have correct identifiers and deidentification. 3 3. Emission Scan direction (skull->feet or reverse) is not uniform between baseline and follow-ups. (Minor if consistent) 4 31

OSU ICL Quality Check Report Quality check report 32

Excel Tracking Sheet ICL Data Receipt Confirmation SOP 33

CALGB Imaging Data De-Identification Workflow PT name Patient ID Operator Patient address Endpoint Data Analysis Performing physician Images De- Identification Referring physician Institution address Requesting physician Institution Name OSU Imaging Core Lab De-identification Database Tracking 34

ICL CALGB Studies Database Tracking ICL CALGB Studies Database Tracking - continued 35

ICL CALGB Studies Database Tracking - continued Reporting of QA results OSU ICL will keep track of violations and submit a biannual report of violations (major and minor) to.. CALGB QA, IPEC, Imaging PI, Protocol PI, and Imaging Committee Chair. Communication regarding violations should only be made by CALGB staff, Imaging Committee Chair or the ICL. 36