RECIST 1.1 Paul O'Moore, M.D. Introduction to a Method of Response Evaluation in Solid Tumors and A Practical Example of its Use in a Clinical Research Setting Paul O'Moore, M.D. Head of Section Interventional Radiology Abington Hospital Jefferson Health, Abington PA Disclosure: Paid Adjudicator, ICON Clinical Imaging NRG Oncology, Houston, the Great State of Texas, February 2017 1

RECIST = Response Evaluation Criteria in Solid Tumors A REPRODUCIBLE system of measuring tumor burden in investigational subjects Prior to 2000, variability between systems of measurement of tumor volumes made comparison between clinical trial outcomes difficult. RECIST 1.0 published in 2000. Updated to RECIST 1.1 in 2008 (Eisenhauer, EA. Euro J Cancer 45: 2009; 228-247.) Purpose was to provide reproducible, objective measurement of tumor burden either clinically or radiographically. Tumor regression in Phase II trials predicts a higher likelihood of improvement of survival or delayed TTP in Phase III trials. NRG Oncology 2

RECIST 1.1 – Things that are Assessed and Measured Target Lesions (Measurable) Total of 5, 2 per organ: Masses: Minimum Size (longest axis in plane): > 10mm by CT (max slice thickness of 5mm) > 10mm by calipers by clinical exam > 20mm by CXR (obsolete) Lymph Nodes (LN Count as a “Organ” so only 2 can be TL: >15mm in SHORT axis by CT. Only SHORT axis is measured. NRG Oncology 3

RECIST 1.1 – Things that are Assessed but NOT Measured Things that count but aren't included in measurements: Non-Target (Non-Measurable): All other lesions including small lesions ( tumors <10mm or pathological LN >10 and <=15mm) or truly non-measurable lesions like ascites, effusions, lymphatic spread, meningeal spread. Special Lesions: Bone (lytic or mixed lesions with measurable soft-tissue components) can be used as target lesions. Esp. important in Breast Ca. Cystic Lesions can be used as target lesions IF they meet criteria for measurability but solid lesions are preferred. Best avoided. NRG Feb 2017 4

RECIST 1.1 – Some Terminology A little alphabet soup: CR=Complete Response PR=Partial Response PD=Progressive Disease SD=Stable Disease NE=Not Evaluable BOR=Best Overall Response PET/CT=Positron Emission Tomography with CT Correlation NRG Oncology 5

RECIST 1.1 – How to Measure and Follow Lesions Metric notation, Baseline as close as possible to first treatment and always within four weeks of Rx. Imaging always preferred to clinical exam UNLESS lesions cannot be imaged. CT preferred to CXR. (Slices 5mm or less.) CT preferred to MRI but this evolving. MRI parameters must be identical for follow-up. Variability is an issue. US is not used. PET/CT is permitted upgrade to CR in patients with residual lesions if they are negative (inactive). Tumor Markers (CA125) have a special place in Gynecologic Oncology. NRG Oncology 6

RECIST 1.1 – Response Evaluation for Individual Lesions: Measurable Lesions: (Maximum TL=five, two per organ). After 5, any other measurable lesions are Non-Target Lesions. Measurement = Sum of Diameters (long axis for non-lymph node lesions, short axis for LN>15mm). Lesions can disappear and be recorded as 0mm, but LN that are too small to measure yet still present are carried and are recorded as 5mm. Non-Measurable Lesions: (Present, Absent or Unequivocal Progression). Blastic Bone Lesions are not measurible. Soft tissue component of mixed lytic/blastic lesions are measurable. NRG Oncology 7

RECIST 1.1 – Response Evaluation for Individual Lesions: Subsequent Response Assessment: Target Lesions: CR (Gone or LN SA<10mm), PR (>30% decrease in sum of diameters from BL), PD (>20% increase in sum from Nadir and >5mm absolute increase OR New Lesion(s)) or SD <30% decrease and <20% increase). Non-Target Lesions: CR, Non-CR/Non-PD (Persistence), OR PD (Unequivocal Progression) New Lesions: Unequivocally tumor. Appearance at site not imaged at BL is a New Lesion and PD. If equivocal, follow-up may be needed to confirm PD which is dated from first appearance. PET/CT can complement detection of new lesions: If negative BL PET has positive follow-up then this is a new lesion. If no BL PET then Positive PET, this is PD IFF there is a corresponding new lesion on CT OR additional follow-up shows disease at that site. (PD dates from initial positive PET). NRG Oncology 8

RECIST 1.1 – Response Evaluation for Individual Lesions: Measurable Lesions: (Maximum five, two per organ). Measurement = Sum of Diameters (long axis for non-lymph node lesions, short axis for LN>15mm). Lesions can decrease to 0, LN that are too small to measure are recorded as 5mm. Non-Measurable Lesions: (Present, Absent or Unequivocal Progression). Subsequent Response Assessment: Target Lesions: CR (Gone or LN SA<10mm), PR (>30% decrease in sum of diameters from BL), PD (>20% increase in sum from Nadir and >5mm absolute increase OR New Lesion(s)) or SD <30% decrease and <20% increase). Non-Target Lesions: CR, Non-CR/Non-PD (Persistence), PD (Unequivocal Progression) New Lesions: Unequivocally tumor. Appearance at site not imaged at BL is a New Lesion and PD. If equivocal, follow-up may be needed to confirm PD which is dated from first appearance. PET/CT can complement detection of new lesions: If negative BL PET has positive follow=up then this is a new lesion. If no BL PET then Positive PET, this is PD IFF there is a corresponding new lesion on CT OR additional follow-up shows disease at that site. (PD dates from initial positive PET). NRG Oncology 9

RECIST 1.1 – Let's Get Started NRG Oncology 10

RECIST 1.1 – Let's Get Started Baseline Measurements: As close to start of Rx as possible, no more than 4 weeks prior to treatment. Identify all the Measurable Lesions: Longest Diameter >= 10mm. Find some things to measure that are EASY TO MEASURE—Sharp edges. If the largest lesions does not lend itself to easy measurement, select the next largest. Abnormal Lymph Nodes: SHORT AXIS > 15mm. Identify Non-Measurable Lesions that don't meet criteria for measurability: LN >9 and <14mm or Lesions < 10mm Identify Truly Non-Measurable Lesions: Pleural Effusions, Meningeal spread, SLD = Sum of LD's plus LN SD's = BASELINE SLD. NRG Oncology 11

RECIST 1.1 – Let's Get Started Some LN's and Two Solid Lesions NRG Oncology 12

RECIST 1.1 – Let's Get Started Now Talley up the Lesions: Target Lesions: (Maximum five, two per organ). NOTE: Lymph Nodes are ONE ORGAN. So only two LN are Target Lesions. All others are designated non-target. Select Target Lesions that are EASY TO MEASURE and likely to remain EASILY MEASURABLE. Measurement = Sum of TL Target Lesion Diameters (long axis for non-lymph node lesions, short axis for LN>15mm). Lesions can decrease to 0, LN that are too small to measure are recorded as 5mm. Report Slice Location and give Short and Long Axis in MM. Annotate and Save the Images. Make a chart of the lesions that are being followed, separate from the radiology reports. NRG Oncology 13

RECIST 1.1 – Let's Get Started LN's in 39 yo w Breast Ca Ovarian Ca NRG Oncology 14

RECIST 1.1 – Let's Keep Going NRG Oncology 15

RECIST 1.1 – Let's Keep Going All TL & Non-TL are measured – If split, add LAD's, If coalesced report max LAD of combined lesions. If LN's coalesce, take perpendicular of longest diameter as the SAD. All LN are measured – Report SAD even if < 10mm. Even if they return to “normal” (<10mm)-Otherwise they would become “new lesions” if then grow >9mm. Measure anything that's still visible—lesions that are “too small to measure” can be assigned 5mm as long as they are still visible. If they are completely absent then LAD = 0. Non-Target Lesions are either Present / Absent / Unequivocal Progression. Use judiciously in conjuction with disease progression in other lesions as it overrides TL's. If progression is unclear, obtain confirmation at next treatment cycle. PD will be back dated to prior exam. NRG Oncology 16

RECIST 1.1 – Measurements of Target and Non-Target Lesions are Combined to Determine Response at each Timepoint and BOR NRG Oncology 17

RECIST 1.1 – Measurements of Target and Non-Target Lesions are Combined to Determine Response at each Timepoint and BOR NRG Oncology 18

RECIST 1.1 – Measurements of Target and Non-Target Lesions are Combined to Determine Response at each Timepoint and BOR NRG Oncology 19

RECIST 1.1 – Some Fine Points of Measurement Thinner slices are better- 5's for soft tissue lesions-Mandatory Consider 2mm for lung nodules (if you are going to have comparable 2mm cuts on subsequent scans). In this example, 2mm cuts make true edges much easier to define because of volume averaging. Dimensions of lesion are more readily determined as 5 x 8 rather than 5 x 6mm. NRG Oncology 20

RECIST 1.1 – Some Fine Points of Measurement Bigger is Often More Accurate When measured on Non-Zoomed Image, margins of lesions are determined to be 13 x 25mm. NRG Oncology 21

RECIST 1.1 – Some Fine Points of Measurement Bigger is Often More Accurate When measured on Non-Zoomed Image, margins of lesions are determined to be 13 x 23mm. A 2mm difference. NRG Oncology 22

RECIST 1.1 – Some Fine Points of Measurement Bigger is Often More Accurate Even more important when things are shrinking Zoomed Measurement = 6 x 6 mm Non-Zoomed Measurement = 5 x 5 mm 5mm v 6mm = 20% difference. That is the difference between PD and SD at follow-up . NRG Oncology 23

RECIST 1.1 – Some Fine Points of Measurement TIME Matters as Well Sometimes certainty requires another cycle. Four Months Later, Clearly a New Lesion “PD” ?New Small Liver Lesion If in doubt, wait it out. If critical, consider PET. NRG Oncology 24

RECIST 1.1 – Some Fine Points of Measurement PD Considerations in Follow-Up Beware lesions that disappear-keep measuring until they REALLY can't be located. If you can still see them, they'll be carried as (a nominal) 5mm until they are “unable to be located”. Watch out for “lesion drift”—when there are multiple lesions of which only one is being followed (ex. Omental) it is easy to shift attention from the lesion being followed to an adjacent lesion. Errors propagate. Go back to the baseline scan to properly identify the original target or non-target lesion if there is any uncertainly. Best Practice NRG Oncology

Complete Regression and Reappearance = PD RECIST 1.1 – Some Fine Points of Measurement Additional Considerations in Follow-Up Complete Regression and Reappearance = PD But take into account ENTIRE TUMOR BURDEN. If all sites of disease were resolved, reappearance of a new lesion = PD. BUT in PR or SD, one lesion reappearing is not automatically PD—other criteria needed such as truly new lesions or sum of diameters > 20% NRG Oncology

RECIST 1.1 – Some Fine Points of Measurement Special Lymph Node Considerations in Follow-Up If PR or SD: 1. Previously abnormal TARGET that became normal and then enlarged in size to be counted as pathologic and measurable (SAD>=15mm) should be added back to sum of diameters to see of PD criteria are met. 2. Previously abnormal NT node that became normal and then recurred must meet criteria for PD base on NT lesions to call progression. 3. A Normal Node at BL (<15mm) that subsequently becomes abnormal is considered a NEW LESION and results in PD. IF A SINGLE LESION IS DRIVING PROGRESSION, CONTINUE FOLLOW-UP AND CONFIRM PD, Date PD from date the lesion was first documented. NRG Oncology

RECIST 1.1 – Example from a Clinical Trial Steps in the Process: At Baseline: 1. Identify Target and Non-Target Lesions. 2. Record Measurements with Scan Numbers. Annotate the images. Save the annotations. At Follow-Up: 1. Make the chart of identified lesions available to the reader. 2. Have the Reader identify and measure every lesion with scan numbers with saved annotations. Be on the lookout for new lesions. 3. Record measurements and update the database before the next visit. NRG Oncology 28

RECIST 1.1 – Example from a Clinical Trial Patients in Clinical Trials are identified and specially tagged at the time of their scan to alert the Radiologist that a “Research Read” is required. NRG Oncology 29

RECIST 1.1 – Example from a Clinical Trial Example Patient #1 Pelvic tumor measured at Baseline. Annotated on image. Dictated in report. NRG Oncology 30

RECIST 1.1 – Example from a Clinical Trial Baseline Measurements entered into Database (simple Excel spreadsheet available on secure “shared drive”) by Research Staff. NRG Oncology 31

RECIST 1.1 – Example from a Clinical Trial Baseline Measurements entered into Database (simple Excel spreadsheet available on secure “shared drive”) by Research Staff. NRG Oncology 32

RECIST 1.1 – Example from a Clinical Trial Target and Non-Target lesions are measured at subsequent time points, annotated on image and dictated in report. Radiologist has access to all prior measurements. Process continues until PD or trial ends. NRG Oncology 33

RECIST 1.1 – Example from a Clinical Trial Measurements are entered and summed—short axis for Lns and long axis for other measurable lesions. NRG Oncology 34

RECIST 1.1 – Example from a Clinical Trial April May August December NRG Oncology 35

RECIST 1.1 – Example from a Clinical Trial Non-Target Lesions are entered as well. NRG Oncology 36

RECIST 1.1 – Tips and Tricks Identify a Core group of Radiologist that are committed to clinical research, if possible steer the protocol patients to them. Consider making an “on-call” schedule to reduce customer frustration. Try to have 24 hour lead time. Pick clearly defined lesions when feasible. Magnify when measur9ing to better define the “true edge”. Pick lesions that conform to known disease behaviors. Pick wisely. Don't pick things that will “disappear”. Refer back to Baseline Scans as often as possible AND whenever in doubt. Have a centralized index of measurements that is available to everyone. When in doubt, refer back to the Specific Protocol. Follow the Rules. Yes, there's an App for that: www.RECIST.com NRG Oncology 37

RECIST 1.1 – FAQ's ?Report lesions < 5mm or just report 5mm default? Measure and record ALL Nodal and Non-Nodal Lesions at all time points. If a Lesion is NO LONGER SEEN, report as zero or “absent”. If lesions is <5mm and it can still be seen, measure it as best as you can. Zoom way up as needed. If no number can be determined, use 5mm. This will prevent false positive PD in subsequent measurements. ?How to apply two lesion role per organ to LN? LN are ONE ORGAN. Only two LN can be measured as TL. Others become Non-TL. ?What happens when LN coalesce? The vector of the LAD can be used to locate the SAD. ?How big must a LN be to qualify as recurrent disease? LN must be >9mm to qualify as “malignant” and count toward PD. NRG Oncology 38

RECIST 1.1 – Additional Images and Examples Additional cases and examples will be presented if time permits... NRG Oncology 39

RECIST 1.1 – Additional Images and Examples Coalescing Lymph Node Measurement NRG Oncology 40

RECIST 1.1 – Additional Images and Examples Non-Measurable Disease - Mets less than 5mm, Ascites, Pleural Effusion NRG Oncology 41

RECIST 1.1 – SUMMARY RECIST is a method for obtaining reliable, reproducible measurements of tumor burden that can be accurately compared between centers and trials. It correlates with other measures of treatment effectiveness such as TTP and Median Survival It can be implemented locally and easily with a small amount of effort and organized using standard office tools and available Radiology PACS systems tools. NRG Oncology 42

RECIST 1.1 – Additional Images and Examples Measurable Disease – Lytic Bone Met NRG Oncology 43

RECIST 1.1 – Additional Images and Examples Use of PET – From Nishino, et al. AJR 2010; 195; 281-289 NRG Oncology 44

RECIST 1.1 – SUMMARY RECIST is a method for obtaining reliable, reproducible measurements of tumor burden that can be accurately compared between centers and trials. It correlates with other measures of treatment effectiveness such as TTP and Median Survival It can be implemented locally and easily with a small amount of effort and organized using standard office tools and available Radiology PACS systems tools. NRG Oncology 45

RECIST 1.1 – References Eisenhauer EA, at al. New Response Evaluation Criteria in Solid Tumors: Revised RECIST Guideline (Version 1.1). Eur J. Cancer 2009; 45(2): 228-247. Tirkes, et al. Response Criteria in Oncologic Imaging: Review of Traditional and New Criteria. Radiographics 2013; 33:1323-1341. Schwartz LH, et al. RECIST 1.1—Update and Clarification: From the RECIST Committee. Eur J Cancer 2016; 62: 132-137. NRG Oncology 46

RECIST 1.1 THANK YOU! and QUESTIONS? Paul O'Moore, M.D. Introduction to a Method of Response Evaluation in Solid Tumors and A Practical Example of its use in a Clinical Research Setting THANK YOU! and QUESTIONS? Paul O'Moore, M.D. Head of Section Interventional Radiology Abington Hospital Jefferson Health, Abington PA paul.o'moore@jefferson.edu Special thanks to Dr. Nolte, Dr. Hanjani NRG Oncology, Houston, February 2017 47