1. Response Assessment Criteria for Clinical Trials Tumor Imaging Metrics Core January 29, 2008 Cheryl A. Sadow, MD Abdominal Imaging & Intervention Division Brigham & Women’s Hospital

2. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 2 RECIST Response Evaluation Criteria in Solid Tumors Standardized repeatable method for measuring response to therapy for solid tumors NOT EQUIVALENT TO A CLINICAL READ!!! RECIST is a combination of both qualitative and quantitative assessment Based on concept of target lesions and non-target lesions Target lesions are quantitatively assessed Non-target lesions are qualitatively assessed

3. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 3 RECIST Based on concept of target lesions and non-target lesions Target lesions are chosen based on 3 factors: Must be EASILY (and reproducibly) measurable Must be representative of the disease (clearly metastasis) Must be representative of distribution (choose measurable lesions from all involved organs) Non-target lesions are all other presumed manifestations of the disease All non-measurable lesions Measurable lesions that were not chosen as target lesions Lesions that may be (but not definitely) metastases

4. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 4 Target Lesions Target lesions must be measurable Definition of Measurable Lesions Size Matters Conventional CT or MRI (non-spiral): If slice collimation <10mm, minimum lesion size is 20 mm If slice collimation >10mm, minimum lesion size is 2 x collimation ex. Slice collimation = 15mm, minimum lesion size = 30mm Spiral CT If slice collimation <5mm, minimum lesion size is 10 mm If slice collimation >5mm, minimum lesion size is 2 x collimation ex. Slice collimation = 7mm, minimum lesion size = 14mm

5. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 5 Target Lesions Target lesions must be reproducibly measurable Definition of reproducibly measurable lesions Consistency across time points Pick lesions with well defined edges or margins Always measure longest diameter Measure lesions on same phase or same sequence (MRI) Only measure lesions that are definitely metastases (If unsure don’t measure) Pick lesions that are stable in position, try to avoid mobile lesions (Avoid mesenteric masses that change in position)

6. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 6 Target Lesions Target lesions should represent distribution of disease Definition of measurable lesions Representative of disease throughout body Pick lesions from disparate areas of the body Do not choose > 5 lesions in any one organ or anatomic location Organs are well defined Anatomic regions are up to individual interpretation (use best judgment) For lymphoma choose nodes from different nodal stations

7. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 7 Target Lesions Measurable lesions up to a maximum of 5 lesions per organ 10 lesions total Select based on size and reliability of measurement Sum of longest diameter (SLD) for all target lesions will be calculated at baseline and used as reference to characterize objective tumor response

8. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 8 Quantitative Assessment The “SLD” is the quantitative assessment SLD = sum of the longest diameters of target lesions This part of the evaluation is not subject to interpretation Strict rules and definitions of: Complete response = No measurable disease Partial Response = Greater than 30% decrease in score Stable Disease = Between 30% decrease and 20% increase Progression = Greater than 20% increase in score

9. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 9 Non – Target Lesions All aspects of disease not chosen as Target Lesions All non-measurable lesions Measurable lesions that were not chosen as target lesions Lesions that may be (but not definitely) metastases Non- measurable lesions Not suitable for accurate repeated measurements Ascites Leptomeningeal disease Pleural effusions Inflammatory breast disease Cystic lesions Lymphangitis cutis/pulmonis Bone lesions Brain lesions Irradiated lesions Ground glass lung lesions

10. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 10 Measuring Lesions Baseline Scan – Initial Review Determine if a single measurable lesion is present Once single lesion is found, no need to evaluate any further Baseline scan – Full Review Determine target lesions and non-target lesions Target lesions Record site and longest diameter Measure longest diameter (LD) on slice where the lesion is largest Use magnification and appropriate window/level Non-target lesions Record site and description Will be assessed qualitatively in the future

11. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 11 Follow-up: Target Lesions On follow-up scans, once a lesion is identified as Target: Must continue to measure even if LD falls below size criteria Measure LD regardless of location (slice) or orientation on prior scan Choose slice where lesion is largest, even if different than baseline Measure LD regardless of poor image quality or poorly defined lesion boundaries (i.e., if target lesion is imaged, LD must be measured) If a target lesion is visible but too small to measure, list as “5mm” If lesion is not imaged, enter “Unknown” (outside FOV) If “unknown” is entered, comments are required

12. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 12 Follow-up Scans Target lesions on follow-up: If a lesion separates to form discrete lesions, measure LD of each lesion and report separately (e.g. #3 -> 3 and 3a) If target lesion becomes confluent, measure LD of lesion and record under 1 of the lesions and enter “0 mm” for other lesion(s) Non-target lesions on follow-up: All lesion region or organ that were selected will be followed and their status will be recorded as: Absent: If totally resolved (CR) Unchanged, Improved, or ? increased but not clearly increased (SD) Clearly worse: Indicative of progression (PD) Not assessed: Missing, incomplete imaging (UN)

13. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 13 Follow-up Scans New lesions seen on follow-up: Any lesion that appears after baseline (including new lesions in irradiated areas) Any lesions that re-appear will be considered new lesions Lesions should be greater than the slice thickness (usually at least 6 mm) to be considered a new lesion

14. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 14 Measuring Lesions Liver lesions: Include the hypervascular peripheral component Measure in portal venous phase on CT Measured in post contrast T1 axial images (portal phase)

15. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 15 Tumor Response - Target Lesions Complete response (CR): Disappearance of all target lesions Partial response (PR): > 30% decrease in the SLD taking as reference the baseline SLD Stable decrease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD Progression (PD): > 20% increase in the SLD taking as reference the nadir beginning with baseline measurement (if unknown is present then that SLD cannot be used as reference) Unknown (UN): If one or more unknown is present and the SLD is not indicative of PD (explanatory comments required)

16. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 16 Tumor Response – Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions Incomplete Response/Stable Disease (SD): If one or more is Unchanged or Improved and no PD, “not assessed” or “not done” Progression (PD): If at least one “Clearly worse” is present Unknown (UN): If “not assessed” or “not imaged” is present

17. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 17 Tumor Response – New Lesions New Lesions = Progression (PD) Any new malignant lesion Any re-appearing lesion

18. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 18 Tumor Response - Summarized Target Lesions Non-target Lesions New Lesions Overall Response CR NoCR SDNoPR CR or SDNoPR SDCR or SDNoSD PDAny Yes or No PD AnyPD Yes or No PD Any Yes (PD) PD

19. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 19 Surgery & Radiotherapy Note: If at all possible, lesions in areas of known radiation or surgery should not be selected as target or non-target lesions

20. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 20 Pleural Effusion & Ascites Note: New or enlarging pleural effusions or ascites evidenced radiographically will NOT be assumed to be malignant

21. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 21 Cheson Criteria Based on International Working Group Recommendations Standardized repeatable method for measuring response to therapy for NHL Response is assessed on 3 criteria: 1Radiological Lymph nodes/Quantitative masses 2ClinicalPhysical ExamQualitative Spleen/Liver Biochemical 3PathologicalBone Marrow Semi-quantitative

22. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 22 Node Selection Must be representative of the distribution of the disease Must be clearly and reproducibly measurable in at least 2 perpendicular dimensions Definition of Target Lesions Abnormal lymph nodes and/or nodal masses and/or hepatic/splenic nodules (up to 6) >1.5 cm longest diameter and >1.0 cm transverse diameter Mediastinal and retroperitoneal areas of disease should be included whenever these sites are involved Definition of Non-target Lesions Except for splenic or hepatic nodules, involvement of other organs is considered non-measurable disease Any lymph nodes or nodal masses not selected as target lesions

23. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 23 Tumor Assessment – Response Criteria Radiological Criteria = Lymph Nodes / Masses CR 1.5 cm at baseline, or 75% decrease in SPD at baseline CRu>1.5 cm LD that has regressed by >75 % in (unconfirmed)SPD at baseline PR>= 50% decrease in SPD at baseline of 6 largest dominant nodes or nodal masses No increases in other nodes PD >= 50% increase in SPD from nadir and/or appearance of any new lesion SDLess than PR but not progression

24. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 24 Tumor Response - Summarized Response category Physical Evaluation Lymph Nodes Lymph Node Masses Bone Marrow CRNormal CRuNormal Indeterminate Normal >75% decrease Normal or Indeterminate PRNormal Positive Normal >=50% decrease Irrelevant Decrease in liver/spleen >=50% decrease Irrelevant Relapse/ Progression Enlarging liver/spleen; new sites New or Increased Reappearance

25. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 25 Reviewer Selection Criteria Per ICH Guidelines Chosen according to ICH Guidelines & other regulation Reviewers MUST have No financial interest in the outcome of the study No involvement in study design and conduct Agreed to no use of information learned during the course of the trial without approval by sponsor M.D. with appropriate medical expertise in clinical area

26. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 26 Data Form Requirements Reviewer is responsible for accuracy of data entered on the form Upon completion, reviewer must sign the form Any changes necessary (once the CRF is signed) will be considered a re-review All changes must be initialed and dated

27. Copyright © 2008 TIMC, Matthew A. Barish M.D. All rights reserved. 27 Thank you for your attention