my department presentation

1. Response evaluation in solid tumors PRESENTER: DR.B.SATHISH (JR,1ST Yr RT) MODERATOR:DR.ASHUTOSH MUKHERJEE, Asst Prof RT

2. Why Measure Response? The word “response” is used in a number of contexts: To describe outcomes in daily practice (“my patient is responding to treatment”) and make decisions about continuing therapy As a surrogate for benefit (e.g. in randomized trial) As the primary endpoint in phase II “screening” trials

4. PHASE II

7. PHASE III

10. Expanded Treatment Groups

11. Under studied groups (racial/gender)

12. Long term benefit

13. Long term risk

15. Response Criteria in Clinical Trials Mid-late 1990s: International working group began to meet to address some shortcomings of WHO. For example: Complexity (bidimensional measurements) New technologies (CT) Silent on many areas so open to varying interpretation i.e. the “standard” was no longer the standard

16. Response Evaluation Criteria in Solid Tumors: “RECIST” Working Group 1995: International representation from different research organizations Revisit definitions, assumptions, implications Harmonize to the best standards Simplify where possible Update with new concepts An ongoing process………

21. Measure the longest in plane diameter

22. Measurable lesion The round shape and sharp boundaries of this lung lesion (arrow) makeit ideally suited for linear measurement.

23. Target Lesions Target lesions must be reproduciblymeasurable 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)

25. Target Lesions Target lesions should represent distribution of disease Representative of disease throughout body Pick lesions from different areas of the body Do not choose > 2 lesions in any one organ or anatomic location Organs are well defined For lymphoma choose nodes from different nodal stations

27. Pericardial effusion• Leptomeningeal disease

28. Pleural effusions • Inflammatory breast disease

29. Cystic lesions •Lymphangitis cutis/pulmonis

30. Bone lesions • Brain lesions

32. Special considerations Lytic bone lesions with soft tissue component which meets the definition of measurability by CT /MRI can be considered measurable Blastic bone lesions are not measurable Simple cysts are not considered malignant so not taken as targets Cystic metastases meeting the criteria can be considered but if non cystic lesions are present they are preferred as targets

33. Clinical evaluation Considered measurable only if superficial(e.g. skin nodules and lymph nodes) 10mm minimum size by caliper measurement{if immeasurable by calipers it is termed as non-measurable} Documentation with color photo and ruler is needed Imaging is always better than clinical assessment

34. CXR Measurable lesion 20 mm minimum size Clearly defined Surrounded by aerated lung Full inspiration, PA view with constant tube- chest distance at every follow up

35. Best modality

36. Ct scan If 5mm slice thickness then the lesion should be minimum 10mm Minimum size of lesion>=double slice thickness LD is selected in axial plane only Para spinal tumors are better measured in coronal/sagittal plane Lesions bordering chest wall and mediastinal lesions(don’t use CXR as slight motion can affect interpretation) Oral and iv contrast to accentuate bowel/vessels against soft tissue mass is routinely done Most abdominal images are taken in the portal venous phase

37. MRI Complex issue MRI Scanners vary in images produced based on Magnet strength Coil design Patient cooperation Motion artifacts Use same scanner and same anatomical plane As far as possible use a CT scan IOC for follow up of breast lesions in NACT (not CT or mammogram)

38. USG Not used in clinical trials because interpretation is subjective Alternative to clinical measurements for Superficial palpable lymph nodes Subcutaneous lesions Thyroid nodules To confirm disappearance of superficial lesions assessed clinically If there is a paraaortic node and distended bowel USG wont detect it and so downstage the disease Reproducibility of entire examination at later date not accurate

39. Endoscopy and laparoscopy Not yet been fully or widely validated Requires expertise and restricted availability Can be used to confirm CR by taking biopsy

40. Tumor markers Cant be used alone to assess response Specific guidelines for PSA and CA125 have been published Gynecological cancer intergroup has developed CA125 progression criteria which are to be integrated with objective tumor assessment for use in first line trials in ovarian cancer

41. hpe To differentiate partial vs. complete response in rare cases(e.g. residual tumors can be benign in germ cell tumors) Worsening effusion in stable disease or responded disease needs cytology to differentiate progression vs. drug induced e.g. taxanecompunds

42. Measuring Lesions Baseline Scan – Initial Review Determine if a single measurable lesion is present Once single lesion is found, confirm the neoplastic nature by biopsy Baseline assessment never >4weeks before the beginning of treatment 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

43. Malignant lymph nodes To be considered pathological a lymph node must be >=15mm in short axis by CT scan with slice thickness not more than 5 mm Only short axis is measured at baseline and follow up(e.g. for an abdominal node 20*30 mm size 20mm is taken as short axis) Multiple lesions in single organ can be recorded as single item e.g. multiple pelvic nodes/multiple liver mets

44. LYMPH NODE ASSESSMENT THE SOLID LINE IS THE SHORT AXIS

45. Short axis is 45.316

46. Example: 10 Lesions

47. Tumor Response - Target Lesions Complete response (CR): Disappearance of all target lesions and any pathological LN(target or non target must have <10 mm short axis) Partial response (PR): >= 30% decrease in the SLD taking as reference the baseline SLD Progression (PD): >= 20% increase in the SLD taking as reference the smallest SLD since beginning of treatment and also a minimum absolute increase of 5mm Stable decrease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest SLD since beginning of treatment Unknown (UN): If one or more unknown is present and the SLD is not indicative of PD (explanatory comments required)

48. 6 cm CR PR 3cm 5cm SD PD 9cm 7cm

49. Tumor Response – Non-Target Lesions Complete Response (CR):Disappearance of all lesions and normalization of all tumor marker levels and lymph nodes <10 mm in short axis Non CR/Non-PD :persistence of one or more lesions and/or maintenance of tumor markers above normal limits Progression (PD):appearance of new lesions and/or unequivocal progression of existing lesions Unknown (UN): If “not assessed” or “not imaged”

52. baseline Follow up

53. Splitting and merging

54. merging

55. 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 If a lesion reappears after CR then it is PD If lesion reappears in PR/SD measure its LD and add to SLD to assess response No miminum diameter is needed for a new lesion and if equivocal repeat CT in the next visit and get a radiologist opinion

56. Missing assessments and in evaluable designation No imaging done at protocol specified time point-non evaluable(NE) Not all lesions measured at follow up-NE(conditions apply) Lost to follow-up : in evaluable

57. Special scenarios If global deterioration of health requiring Rx discontinuation then it is classified as symptomatic deterioration It is not an objective response but a reason to discontinue therapy If u cant differentiate normal tissue from residual disease/scarring-- biopsy/PET scan is done before calling it as complete response If equivocal findings at follow up wait till next follow up to confirm PD,SD or PR If solid lesion becomes necrotic still measure LD and make a note of the necrosis

58. Importance of iv contrast

59. Continue measuring even if cavity develops

60. Frequency of reevaluation Protocol specific Which organ? How often? Goal of trial - response or TTP/PFS? Routine calendar scheduled re-evaluation In phase 2 studies follow up every 6-8 weeks is an acceptable norm

61. Confirmation of response Particularly useful in non randomized trials where response in the primary end point To ensure that response is not a measurement error If criteria for CR or PR are met reassess in no less than 4 weeks to confirm response If SD then criteria must be met at least once after study entry at a minimum interval defined by study protocol

62. Duration of overall response From the time the criteria for CR/PR is met first till the day 1 of objectively documented PD or recurrence Duration of SD- time from start of Rx/date of randomization till the criteria for PD are met The response is reviewed by a panel of experts independent of the study

63. Pfs and ttp Baseline estimation of expected PFS/TTP without treatment Methodology to be applied should be thoroughly described in the protocol

64. Reporting results CR PR SD PD Inevaluable for response Early death from malignancy Early death from toxicity Early death due to some other cause Unknown(not assessable,insufficent data) (1- 4 are called eligible patients to calculate response rate)

65. Tumor Response – Summarized

66. Issues Arising since RECIST Implementation Minimum number of lesions: Can fewer than 5 lesions be assessed? Use of RECIST in randomized trials Use of newer imaging technologies such as PET and MRI. Use of RECIST in trials of non-cytotoxic drugs.

67. Example: 10 Lesions

68. Example: 6 largest selected

69. Example: 3 largest selected

70. RECIST in Randomized Trials This presents two issues: Can rigorous response assessment requirements be relaxed? How to assess progression in patients who do not have measurable lesions?

71. Measuring Objective Response in Phase III Trials If objective response is the end point then use RECIST 1.1 If objective response is not the primary endpoint, then method of reporting results should be pre-specified in the protocol

72. Progression in Phase III Trials Important issue, since as noted PFS and TTP becoming common primary endpoints. No problem if entry is restricted to patients with measurable lesions! What about patients with non-measurable disease only?

73. Progression in Non-Measurable Disease Fundamental problem: how to measure an increase in that which is not measurable? Options: Count “new disease” only Look for “unequivocal progression” of non-measurable lesions: subject to external review Something else? Go back to using overall survival?

74. What about Functional Changes? RECIST: Based on anatomical tumoursize Does not take into account metabolic function Does not take into account blood flow parameters

75. Are RECIST Applicable in Trials of Non-Cytotoxics? One does not need new “response criteria” for assessing non-cytotoxics One may need to change the “usual” hypotheses that drive phase II design….so instead of a response rate of interest of 20% (typical for many cytotoxic phase II trials), we could: Look for PR + CR rate of 10% Look for SD rate >50% Look for CR + PR + SD rate >60% (or whatever seems meaningful)

76. What HAS changed in RECIST 1.1

78. Limitations of RECIST guidelines Tumor morphology Confluent, Irregular borders Unusual configuration; Circumferential (e.g. mesothelioma) Lesion length > 1.5-2 times lesion width Discordant results due to RECIST technique Uni-dimensional measurement Shape changes may confound results Non-spherical, asymmetric tumor growth Tumor size: Sub-centimeter tumors Choosing representative tumor burden Problematic when tumor burden is substantial Unpredictable Tumor Behavior Differential tumor shrinkage/growth

79. Future? RECIST-Unidimensional WHO-Bidimensional Volumetric

80. Thank you