Full recist violet

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Full recist violet

  1. 1. Response evaluation in solid tumors <br />PRESENTER: DR.B.SATHISH<br />(JR,1ST Yr RT)<br />MODERATOR:DR.ASHUTOSH MUKHERJEE,<br />Asst Prof RT<br />
  2. 2. Why Measure Response?<br />The word “response” is used in a number of contexts:<br />To describe outcomes in daily practice (“my patient is responding to treatment”) and make decisions about continuing therapy<br />As a surrogate for benefit (e.g. in randomized trial)<br />As the primary endpoint in phase II “screening” trials<br />
  3. 3. Why Measure Response?<br />The word “response” is used in a number of contexts:<br />To describe outcomes in daily practice (“my patient is responding to treatment”)<br />As a surrogate for benefit (e.g. in randomized trial)<br /><ul><li>As the primary endpoint in phase II “screening” trials where a decision is being taken about future of drug or regimen.RECIST criteria developed for this</li></li></ul><li>phase I<br />
  4. 4. PHASE II<br />
  5. 5.
  6. 6.
  7. 7. PHASE III<br />
  8. 8.
  9. 9. PHASE IV<br /><ul><li>“Post-Marketing” Studies
  10. 10. Expanded Treatment Groups
  11. 11. Under studied groups (racial/gender)
  12. 12. Long term benefit
  13. 13. Long term risk
  14. 14. Low frequency toxicity</li></li></ul><li>history<br />Early attempts 1960s<br />Pre imaging era –blood was used to assess tumor response <br />WHO first published tumor response criteria for solid tumors in 1981<br />RECIST was presented in 1999 to ASCO and published in 2000<br />RECIST VERSION 1.1 published in October 2008<br />
  15. 15. Response Criteria in Clinical Trials<br />Mid-late 1990s: International working group began to meet to address some shortcomings of WHO. For example:<br />Complexity (bidimensional measurements)<br />New technologies (CT)<br />Silent on many areas so open to varying interpretation <br />i.e. the “standard” was no longer the standard<br />
  16. 16. Response Evaluation Criteria in Solid Tumors: “RECIST” Working Group<br />1995: International representation from different research organizations<br />Revisit definitions, assumptions, implications<br />Harmonize to the best standards<br />Simplify where possible<br />Update with new concepts<br />An ongoing process………<br />
  17. 17. RECIST version 1.1<br />Response Evaluation Criteria in Solid Tumors<br /><ul><li>Standardized repeatable method for measuring response to therapy for solid tumors
  18. 18. NOT EQUIVALENT TO A CLINICAL READ!!!</li></ul>RECIST is a combination of both qualitative and quantitative assessment<br />Based on concept of target lesions and non-target lesions<br /><ul><li>Target lesions are quantitatively assessed
  19. 19. Non-target lesions are qualitatively assessed</li></li></ul><li>Key RECIST Elements<br />One-dimensional measurement of longest diameters<br />Measurable lesion > 10 mm (5 mm Spiral CT)<br />Identify up to 5 measurable lesions; maximum 2 per organ. Follow sum of longest diameters (SLD)<br />The “SLD” is a quantitative assessment<br />Major application intended for trials where response is primary endpoint<br />Separate criteria used for malignant lymphoma so RECIST not used<br />Can be used in brain tumors but separate criteria are also published<br />
  20. 20. Target Lesions<br /><ul><li>Target lesions are chosen based on 3 factors:</li></ul>Must be EASILY (and reproducibly) measurable<br />Must be representative of the disease (clearly metastasis)<br />Must be representative of distribution (choose measurable lesions from all involved organs)<br />Target lesions must be measurable<br />Definition of Measurable Lesions<br />Size Matters <br />Conventional CT or MRI (non-spiral):<br />If slice collimation <10mm, minimum lesion size is 20 mm<br />If slice collimation >10mm, minimum lesion size is 2 x collimationex. Slice collimation = 15mm, minimum lesion size = 30mm<br />Spiral CT<br />If slice collimation <5mm, minimum lesion size is 10 mm<br />If slice collimation >5mm, minimum lesion size is 2 x collimationex. Slice collimation = 7mm, minimum lesion size = 14mm<br />16<br />
  21. 21. Measure the longest in plane diameter<br />
  22. 22. Measurable lesion<br />The round shape and sharp boundaries of this lung lesion (arrow) makeit ideally suited for linear measurement.<br />
  23. 23. Target Lesions<br />Target lesions must be reproduciblymeasurable<br />Definition of reproducibly measurable lesions<br />Consistency across time points <br />Pick lesions with well defined edges or margins<br />Always measure longest diameter<br />Measure lesions on same phase or same sequence (MRI)<br />Only measure lesions that are definitely metastases(If unsure don’t measure)<br />Pick lesions that are stable in position, try to avoid mobile lesions (Avoid mesenteric masses that change in position)<br />
  24. 24.
  25. 25. Target Lesions<br />Target lesions should represent distribution of disease<br />Representative of disease throughout body <br />Pick lesions from different areas of the body<br />Do not choose > 2 lesions in any one organ or anatomic location<br />Organs are well defined <br />For lymphoma choose nodes from different nodal stations<br />
  26. 26. Non – Target Lesions<br />All aspects of disease not chosen as Target Lesions<br />All non-measurable lesions(LD < 10 mm and LN 10-14mm in short axis)<br />Measurable lesions that were not chosen as target lesions<br />Lesions that may be (but not definitely) metastases<br />Non- measurable lesions<br />Not suitable for accurate repeated measurements<br /><ul><li>Ascites
  27. 27. Pericardial effusion• Leptomeningeal disease
  28. 28. Pleural effusions • Inflammatory breast disease
  29. 29. Cystic lesions •Lymphangitis cutis/pulmonis
  30. 30. Bone lesions • Brain lesions
  31. 31. Irradiated lesions • Ground glass lung lesions</li></li></ul><li>Non measurable lesion<br />
  32. 32. Special considerations<br />Lytic bone lesions with soft tissue component which meets the definition of measurability by CT /MRI can be considered measurable<br />Blastic bone lesions are not measurable<br />Simple cysts are not considered malignant so not taken as targets<br />Cystic metastases meeting the criteria can be considered but if non cystic lesions are present they are preferred as targets<br />
  33. 33. Clinical evaluation<br />Considered measurable only if superficial(e.g. skin nodules and lymph nodes)<br />10mm minimum size by caliper measurement{if immeasurable by calipers it is termed as non-measurable}<br />Documentation with color photo and ruler is needed<br />Imaging is always better than clinical assessment<br />
  34. 34. CXR<br />Measurable lesion<br />20 mm minimum size <br />Clearly defined <br />Surrounded by aerated lung<br />Full inspiration, PA view with constant tube- chest distance at every follow up<br />
  35. 35. Best modality<br />
  36. 36. Ct scan<br />If 5mm slice thickness then the lesion should be minimum 10mm<br />Minimum size of lesion>=double slice thickness<br />LD is selected in axial plane only<br />Para spinal tumors are better measured in coronal/sagittal plane<br />Lesions bordering chest wall and mediastinal lesions(don’t use CXR as slight motion can affect interpretation)<br />Oral and iv contrast to accentuate bowel/vessels against soft tissue mass is routinely done<br />Most abdominal images are taken in the portal venous phase<br />
  37. 37. MRI <br />Complex issue<br />MRI Scanners vary in images produced based on<br />Magnet strength<br />Coil design <br />Patient cooperation<br />Motion artifacts<br />Use same scanner and same anatomical plane<br />As far as possible use a CT scan<br />IOC for follow up of breast lesions in NACT (not CT or mammogram)<br />
  38. 38. USG<br />Not used in clinical trials because interpretation is subjective<br />Alternative to clinical measurements for<br />Superficial palpable lymph nodes<br />Subcutaneous lesions<br />Thyroid nodules<br />To confirm disappearance of superficial lesions assessed clinically<br />If there is a paraaortic node and distended bowel USG wont detect it and so downstage the disease<br />Reproducibility of entire examination at later date not accurate<br />
  39. 39. Endoscopy and laparoscopy<br />Not yet been fully or widely validated<br />Requires expertise and restricted availability<br />Can be used to confirm CR by taking biopsy<br />
  40. 40. Tumor markers<br />Cant be used alone to assess response<br />Specific guidelines for PSA and CA125 have been published<br />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<br />
  41. 41. hpe<br />To differentiate partial vs. complete response in rare cases(e.g. residual tumors can be benign in germ cell tumors)<br />Worsening effusion in stable disease or responded disease needs cytology to differentiate progression vs. drug induced e.g. taxanecompunds<br />
  42. 42. Measuring Lesions<br />Baseline Scan – Initial Review<br />Determine if a single measurable lesion is present<br />Once single lesion is found, confirm the neoplastic nature by biopsy<br />Baseline assessment never >4weeks before the beginning of treatment<br />Baseline scan – Full Review<br />Determine target lesions and non-target lesions<br />Target lesions<br />Record site and longest diameter<br />Measure longest diameter (LD) on slice where the lesion is largest<br />Use magnification and appropriate window/level<br />Non-target lesions<br />Record site and description<br />Will be assessed qualitatively in the future<br />
  43. 43. Malignant lymph nodes<br />To be considered pathological a lymph node must be >=15mm in short axis by CT scan with slice thickness not more than 5 mm<br />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)<br />Multiple lesions in single organ can be recorded as single item e.g. multiple pelvic nodes/multiple liver mets<br />
  44. 44. LYMPH NODE ASSESSMENT<br />THE SOLID LINE IS THE SHORT AXIS<br />
  45. 45. Short axis is 45.316<br />
  46. 46. Example: 10 Lesions<br />
  47. 47. Tumor Response - Target Lesions<br />Complete response (CR): Disappearance of all target lesions and any pathological LN(target or non target must have <10 mm short axis)<br />Partial response (PR): >= 30% decrease in the SLD taking as reference the baseline SLD<br />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<br />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 <br />Unknown (UN): If one or more unknown is present and the SLD is not indicative of PD (explanatory comments required)<br />
  48. 48. 6 cm<br />CR<br />PR <br />3cm<br />5cm<br />SD<br />PD<br />9cm<br />7cm<br />
  49. 49. Tumor Response – Non-Target Lesions<br />Complete Response (CR):Disappearance of all lesions and normalization of all tumor marker levels and lymph nodes <10 mm in short axis<br />Non CR/Non-PD :persistence of one or more lesions and/or maintenance of tumor markers above normal limits<br />Progression (PD):appearance of new lesions and/or unequivocal progression of existing lesions<br />Unknown (UN): If “not assessed” or “not imaged” <br />
  50. 50. Tumor Response – New Lesions<br />Unequivocal New Lesions = Progression (PD)<br /><ul><li>Any new malignant lesion in the same or different site
  51. 51. Any re-appearing lesion</li></ul>PET scan( FDG uptake period of 60 min prior to imaging)<br />-ve baseline but +ve follow up –PD<br />No baseline scan and +ve follow up<br />If it is at a new site then –consider PD<br />If not at the same site additional follow up with CT to confirm PD<br />If follow up CT is negative then it is not PD<br /><ul><li>Best overall response is the best response from the start of treatment until disease progression/recurrence</li></li></ul><li>Follow-up: Target Lesions<br />On follow-up scans, once a lesion is identified as Target:<br />Must continue to measure even if LD falls below size criteria<br />Same method(e.g.CT) of assessment as baseline should be used<br />Measure LD regardless of location (slice) or orientation on prior scan<br />Choose slice where lesion is largest, even if different than baseline<br />Measure LD regardless of poor image quality or poorly defined lesion boundaries (i.e., if target lesion is imaged, LD must be measured)<br />If a target lesion is visible but too small to measure, list as “5mm”<br />If radiologist feels lesion has disappeared record as 0 mm<br />If lesion is not imaged, enter “Unknown” (outside FOV) If “unknown” is entered, comments are required<br />
  52. 52. baseline<br />Follow up<br />
  53. 53. Splitting and merging<br />
  54. 54. merging<br />
  55. 55. Follow-up Scans<br />New lesions seen on follow-up:<br />Any lesion that appears after baseline (including new lesions in irradiated areas)<br />Any lesions that re-appear will be considered new lesions<br />If a lesion reappears after CR then it is PD<br />If lesion reappears in PR/SD measure its LD and add to SLD to assess response<br />No miminum diameter is needed for a new lesion and if equivocal repeat CT in the next visit and get a radiologist opinion<br />
  56. 56. Missing assessments and in evaluable designation<br />No imaging done at protocol specified time point-non evaluable(NE)<br />Not all lesions measured at follow up-NE(conditions apply)<br />Lost to follow-up : in evaluable<br />
  57. 57. Special scenarios<br />If global deterioration of health requiring Rx discontinuation then it is classified as symptomatic deterioration<br />It is not an objective response but a reason to discontinue therapy<br />If u cant differentiate normal tissue from residual disease/scarring-- biopsy/PET scan is done before calling it as complete response<br />If equivocal findings at follow up wait till next follow up to confirm PD,SD or PR<br />If solid lesion becomes necrotic still measure LD and make a note of the necrosis<br />
  58. 58. Importance of iv contrast<br />
  59. 59. Continue measuring even if cavity develops<br />
  60. 60. Frequency of reevaluation<br />Protocol specific<br />Which organ?<br />How often?<br />Goal of trial - response or TTP/PFS?<br />Routine calendar scheduled re-evaluation <br />In phase 2 studies follow up every 6-8 weeks is an acceptable norm<br />
  61. 61. Confirmation of response<br />Particularly useful in non randomized trials where response in the primary end point<br />To ensure that response is not a measurement error<br />If criteria for CR or PR are met reassess in no less than 4 weeks to confirm response<br />If SD then criteria must be met at least once after study entry at a minimum interval defined by study protocol<br />
  62. 62. Duration of overall response<br />From the time the criteria for CR/PR is met first till the day 1 of objectively documented PD or recurrence<br />Duration of SD- time from start of Rx/date of randomization till the criteria for PD are met<br />The response is reviewed by a panel of experts independent of the study<br />
  63. 63. Pfs and ttp<br />Baseline estimation of expected PFS/TTP without treatment<br />Methodology to be applied should be thoroughly described in the protocol<br />
  64. 64. Reporting results<br />CR<br />PR<br />SD<br />PD<br />Inevaluable for response<br />Early death from malignancy<br />Early death from toxicity<br />Early death due to some other cause<br />Unknown(not assessable,insufficent data)<br />(1- 4 are called eligible patients to calculate response rate)<br />
  65. 65. Tumor Response – Summarized<br />
  66. 66. Issues Arising since RECIST Implementation<br />Minimum number of lesions: Can fewer than 5 lesions be assessed? <br />Use of RECIST in randomized trials<br />Use of newer imaging technologies such as PET and MRI. <br />Use of RECIST in trials of non-cytotoxic drugs. <br />
  67. 67. Example: 10 Lesions<br />
  68. 68. Example: 6 largest selected<br />
  69. 69. Example: 3 largest selected<br />
  70. 70. RECIST in Randomized Trials<br />This presents two issues:<br />Can rigorous response assessment requirements be relaxed?<br />How to assess progression in patients who do not have measurable lesions?<br />
  71. 71. Measuring Objective Response in Phase III Trials<br />If objective response is the end point then use RECIST 1.1<br />If objective response is not the primary endpoint, then method of reporting results should be pre-specified in the protocol<br />
  72. 72. Progression in Phase III Trials<br />Important issue, since as noted PFS and TTP becoming common primary endpoints.<br />No problem if entry is restricted to patients with measurable lesions!<br />What about patients with non-measurable disease only?<br />
  73. 73. Progression in Non-Measurable Disease<br />Fundamental problem: how to measure an increase in that which is not measurable?<br />Options:<br />Count “new disease” only<br />Look for “unequivocal progression” of non-measurable lesions: subject to external review<br />Something else? <br />Go back to using overall survival?<br />
  74. 74. What about Functional Changes?<br />RECIST: <br />Based on anatomical tumoursize<br />Does not take into account metabolic function<br />Does not take into account blood flow parameters<br />
  75. 75. Are RECIST Applicable in Trials of Non-Cytotoxics?<br />One does not need new “response criteria” for assessing non-cytotoxics<br />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:<br />Look for PR + CR rate of 10%<br />Look for SD rate >50%<br />Look for CR + PR + SD rate >60%<br />(or whatever seems meaningful)<br />
  76. 76. What HAS changed in RECIST 1.1<br />
  77. 77.
  78. 78. Limitations of RECIST guidelines<br />Tumor morphology<br />Confluent, Irregular borders<br />Unusual configuration; Circumferential (e.g. mesothelioma)<br />Lesion length > 1.5-2 times lesion width<br />Discordant results due to RECIST technique<br />Uni-dimensional measurement<br />Shape changes may confound results<br />Non-spherical, asymmetric tumor growth<br />Tumor size: Sub-centimeter tumors<br />Choosing representative tumor burden<br />Problematic when tumor burden is substantial<br /> Unpredictable Tumor Behavior<br />Differential tumor shrinkage/growth<br />
  79. 79. Future?<br />RECIST-Unidimensional<br />WHO-Bidimensional<br />Volumetric<br />
  80. 80. Thank you<br />

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