How to measure effect of treatment? chest radiography CT scan MRI scan PET scan ultrasound physical examination bone scintygraphy

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1 respons meting Bonne Biesma Franz Schramel Terschelling 2012 How to measure effect of treatment chest radiography CT scan MRI scan PET scan ultrasound physical examination bone scintygraphy guidelines to evaluate the response to treatment in solid tumors Therasse P et al J Natl Cancer Inst 2000;92: Eisenhauer EA et al Eur J Cancer 2009;45: Why measure response The word response is used: To describe outcomes in daily practice ( my patient is responding to treatment ) As a surrogate for benefit (e.g. in randomized trial) As the primary endpoint in phase II screening trials where a decision is being taken about future of drug or regimen WHO vs RECIST in 14 trials tumor response evaluation CR/PR/PD evaluation criteria n RR % PD % WHO RECIST WHO RECIST Why Measure Response The word response is used: To describe outcomes in daily practice ( my patient is responding to treatment ) As a surrogate for benefit (e.g. in randomized trial) 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 RECIST 1.1 1

2 What are your target lesions Do not necessarily select the largest lesions as targets. Select those that are best defined and reproducibly measurable. Deze laesie is evalueerbaar volgens RECIST 1.1 Voor RECIST 1.1 bepaal je 10 target lesions met maximaal 2 per orgaan baseline evaluation 14x9 25x14 10x10 what are your targets 17x16 37x32 Chest X-ray lesions on CXR are acceptable when they are clearly defined and surrounded by aerated lung lesions bordering the chest wall/mediastinum are not suitable CT is preferable target lesions measurable lesions up to 2 lesions per organ 5 lesions total, representative of all involved organs selected on basis of size (longest diameter) suitable for accurate repeated measurement it is best to choose a well-defined isolated lesion Voor RECIST 1.1 is een lymfklier een target lesion als de kortste as 15 mm is 2

3 measuring lymph nodes RECIST 1.1 Measurability RECIST 1.1 enlargement of lymph nodes is surrogate indicator for metastasis short axis is the best predictor of metastatic disease 15 mm: target lesion mm: non-target lesion < 10 mm: non pathologic measure shortest diameter for response evaluation Also shortest diameters < 10 mm during response measurement should be recorded largest diameter only, CT 10 mm (slice thickness 5 mm) non-measurable Blastic bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, inflammatory breast disease, lymphangitis, (cystic lesions), abdominal masses not confirmed/followed by imaging techniques lesions in previously irradiated regions might or might not be considered measurable according to protocol Botmetastasen zijn volgens RECIST 1.1 niet evalueerbaar Which level 135mm 90mm 122mm Volgens RECIST 1.1 zijn pleuravocht en ascites nu wel evalueerbaar bone mets Een laesie moet bvk steeds op hetzelfde niveau gemeten worden Lytic bone lesions, with an identifiable soft tissue component, evaluated by CT or MRI, can be considered as measurable lesions if the soft tissue component otherwise meets the definition of measurability previously described. Blastic bone lesions are non-measurable 3

4 Target measurement rules at follow-up Do not measure across normal tissue pre-treatment pre-treatment post-treatment Splitting Lesions post-treatment The individual longest diameters of all the resulting lesions shall contribute to the sum of diameters (SOD) Er zijn conform RECIST 1.1 target lesions gemeten Merging Lesions non target lesions measurable disease exceeding maximum accepted number (>2 per organ, >5 total) no need to measure in follow-up, but change should be noted non measurable disease overall response consists of target and non-target lesions. The resulting longest diameter accounts for the contribution of ALL involved target lesions to the sum of diameters (SOD) * * * * = alleen onmiskenbare progressie is PD 4

5 Is RECIST gecorreleerd aan prognose Response on CT vs histology patient C august 2009:stage IV adenoca of the right lower lobe. september 2009 start carboplatin/paclitaxel/bevacizumab, (NVALT-12). CT-scan after 4 courses William WN et al. JTO 2013;8:222 Response on CT vs histology Response on CT vs histology and prognosis pre-treatment What is the response post-treatment RECIST unreliable in predicting OS and histopathologic response Limited role in trials as endpoint for efficacy 88mm 71mm N=160, NSCLC, induction chemotherapy followed by resection William WN et al. JTO 2013;8:222 William WN et al. JTO 2013;8:222 Continue measuring target lesions in their longest diameter, even when they develop central cavities or necrosis. If the sum of diameters does not accurately reflect the patient s response assessment, a different assessment may be provided, accompanied by explanatory comments justifying so Response on CT vs histology Wanneer voldoet RECIST niet meer cavitation William WN et al. JTO 2013;8:222 Crab CJ et a; JCO 2008;27:404 5

6 pre-treatment post-treatment Patient NVALT12 study after 2 cycles of CT FDG-PET and RECIST It is sometimes reasonable to incorporate FDG-PET to complement CT scanning in assessment of progression Negative PET at baseline, with a positive PET at follow-up is PD based on a new lesion % afname 48mm 71mm 4.5 cm No PET at baseline and a positive PET at follow-up: 1. If the positive PET at follow-up corresponds to a new site of disease on CT, this is PD. 2. If the positive PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal PET scan). 3. If the positive PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD. cavitation Patient NVALT-12 Baseline Crab CJ et a; JCO 2008;27:404 Patient NVALT-12 Baseline Patient NVALT-12 after 1 cycle of CT PET Response Criteria strong relationship between 18F-FDG uptake and cancer cell number decline in tumor 18F-FDG uptake with a loss of viable cancer cells inability of 18F-FDG to detect minimal tumor burden versus no tumor burden 4.3 cm 6

7 PET Response Criteria What do we need to measure Progressive disease the time to normalization of the PET scan reflects the rate of cell kill and predicts the likelihood of cure patients whose scans rapidly normalize are those most likely to have a favorable outcome, a disease-assessment scan performed soon after the beginning of treatment provides much information predictive of subsequent outcomes Hottest single tumor lesion (SUL) Maximal 1.2cm diameter volume ROI in tumor (SUL peak) SUL peak >1.5 greater than liver SUL (right lobe) Post treatment max SUL needs not to be assessed in the same region Target 30% SUL peak 0.8 SUL units All other Visible increase in extent of FDG uptake New lesions What do we need to measure Complete respons Pt A: CT voor start therapie SUV Standard uptake value (corrected for total body mass) Factors that affect SUV Uptake time Blood glucose levels Body weight Injection technique Camera calibration Region of interest (ROI) Reconstruction method etc target Complete resolution of FDG uptake, that is less than the liver activity All other Disappearance of all other lesions to background No new lesions Tumor 5.8 cm What do we need to measure Partial respons Pt A: CT na 2 kuren Ipilimumab SUL Lean body mass corrected SUV SUL peak Target 30% SUL peak 0.8 SUL units All other No 30% SUL or size No new lesions Tumor 4.3 cm 7

8 Pt A: CT na 2 kuren Ipilimumab Ipilimumab: mechanism of action Response in mesothelioma T-cell activation T-cell inhibition T-cell potentiation CTLA4 T cell T cell T cell APC TCR MHC CD28 B7 APC TCR MHC CD28 CTLA4 TCR B7 MHC APC CTLA4 IPILIMUMAB B7 blocks CTLA-4 Ipilimumab with carbo/paclitaxel in NSCLC; randomized phase II Immune related response criteria Base line Sum of 2 largest perpendicular diameters (SPD) Subsequent assessments SPD index lesions New measurable lesions (up to 5/organ), after ruling out irpd Response evaluation in mesothelioma Despite simple use, application of the RECIST criteria is not simple in pleural mesothelioma Which one is the longest diameter The rich fibrous tissue in the tumour will shrink = hemithorax will get smaller = LD will DECREASE in size! Outer extension of hemithorax can change measurements falsely in responsive patients Ipilimumab followed by ipi/carbo/paclitaxel vs carbo/paclitaxel Lynch TJ et al. JCO 2012;30:2046 Wolchok JD et al. Clin Cancer Res 2009;15:7412 Novak AK. Lung Cancer 2005; 49S1: S37. van Klaveren RJ. Lung Cancer 2004; 43: 63. Ipilimumab in treatment of cancer Immune related response criteria Response evaluation in mesothelioma CTLA-4: Down-regulates T-cell activation Ipilimumab(Yervoy): Fully human monoclonal antibody Blocks CTLA-4 receptor Potentiates T cell activation Korman, Peggs and Allison: Adv. In Immunol. 2006;90: Wolchok JD et al. Clin Cancer Res 2009;15:7412 Monetti F. Lung Cancer 2004; 43: 71. van Klaveren RJ. Lung Cancer 2004; 43: 63. 8

9 Response evaluation in mesothelioma Tumor thickness perpendicular to the chest wall or mediastinum, Two seperate positions at three seperate levels on thoracic CT scan, Sum of six = pleural unidimensional measure. Response evaluation in mesothelioma In 73 patients, response according to modified RECIST criteria predicted for superior survival in responders than non-responders (15.1 versus 8.9 months; p=0.03) and a signficiant correlation between change in linear tumor measurement and FVC was seen (R=0.63, p=0.0001). Byrne MJ. Ann Oncol 2004; 15: 257. M. Metintaş Archive Response evaluation n=34 Cddp/gemcitabine, Cddp, Cddp/tomudex 27% discrepancy between WHO and RECIST 24% PD missed by RECIST WHO: bidimensional RECIST: unidimensional Modified RECIST: short axis perpendicular to chestwall Van Klaveren RJ et al. Lung Cancer 2004;43:63-9 9