Interpretazione dell’imaging radiologico dopo terapie a bersaglio molecolare DANIELE REGGE

2. Interpretazione dell’imaging radiologico dopo terapie a bersaglio molecolare DANIELE REGGE INSTITUTE FOR CANCER RESEARCH AND TREATMENT CANDIOLO-TORINO, ITALY

3. Rationale of cancer therapy Since most cancer treatments, especially chemotherapies, have safety risks, a necessary condition that must be satisfied for a patient to accept treatment is that improvement in terms of relevant and reliable clinical benefits will outweigh the harm done by the treatment.

4. Rationale of cancer therapy • Direct measures of how a patient feels, is able to function, or whether he or she survives following treatment are considered the only definite and meaningful endpoints of clinical benefit. • Therefore, it would be logical to expect that most of the evidence provided by clinical research would be based on measures of definite clinical benefit important to the patients, expressed in terms of gains in survival and in the quality of life.

5. Surrogate end-points • To detect a clinically meaningful and statistically significant difference in OS the required sample sizes, length of follow-up, and associated costs are often considered to be unaffordable. • Surrogate endpoints are indirect measures of definite or true clinical benefit. • Also called intermediate endpoints, surrogate markers, or biomarkers, comprise laboratory, imaging, and physical measurements considered as suitable substitutes for a clinically meaningful endpoints.

6. Surrogate end-points • The validation of surrogate endpoints has received increasing attention due to the harm caused by treatments whose efficacy was assessed using non-validated surrogate endpoints. Grimes DA, Schulz KF (2005) Surrogate end points in clinical research: hazardous to your health. Obstet Gynecol 105:1114-1118

7. Surrogate end-points Surrogate Endpoints of Clinical Benefit Giovannino Ciccone and Ileana Baldi, From Imaging Tumor Response to Therapy, Springer 2012

8. Surrogate end-points Grimes DA, Schulz KF (2005) Surrogate end points in clinical research: hazardous to your health. Obstet Gynecol 105:1114-1118

9. Surrogate end-points Surrogate Endpoints of Clinical Benefit Giovannino Ciccone and Ileana Baldi, From Imaging Tumor Response to Therapy, Springer 2012

10. Surrogate end-points The above-described experience highlights the critical dilemma surrounding the role of surrogate endpoints in clinical research: on the one hand, they have the potential to make new therapies more rapidly available to patients, but on the other they carry the risk of disseminating useless or harmful treatments, with negative consequences for patients and contributing to the waste of scarce resources. Surrogate Endpoints of Clinical Benefit Giovannino Ciccone and Ileana Baldi, From Imaging Tumor Response to Therapy, Springer 2012

11. IMAGING • The aim of using imaging as a surrogate biomarker for the response to treatment in oncology is threefold: • To obtain a measure of disease extent as a function of treatment that is more objective and reproducible than achieved by considering symptoms or clinical status. • To better understand tumour at an earlier time than is possible with other biomarkers or with primary end-points, such as overall survival/mortality or disease-specific survival/mortality. • To reduce, as the combined consequence of points 1 and 2, either the time or the sample size in clinical trials testing new therapies, including drugs, surgery, or imaging-guided interventional procedures. Surrogate Endpoints of Clinical Benefit Giovannino Ciccone and Ileana Baldi, From Imaging Tumor Response to Therapy, Springer 2012

12. IMAGING: WHO criteria (1979-1981) • [(Cross-productFollow-up – Cross-productBaseline)/Cross-productBaseline] x 100 • In case of multiple lesions in an individual patient, cross-products were summed.

13. RECIST 1.0 (year 2000) • Response Evaluation Criteria for Solid Tumors • From 2D to 1D (step backward?) • Use of CT or MRI • Sum of multiple measurements (maximum of 10 target lesions/5 per organ) • Minimum size for target lesions (10mm for spiral CT; 20mm for non spiral CT and MRI) • Non target lesions were considered as non measurable lesions

14. RECIST 1.0 (year 2000)

15. 2D >>> 1D, a step backward? 1st reader 3cmx4cm = 12cm2 2nd reader 3,45cmx4,6=15,87cm3 T1 T2 WHO = 15,87cm2-12,0cm2/12,0cm2=0,32 i.e. PD (≥ 25%)

16. 2D >>> 1D, a step backward? 1st reader 3cmx4cm = 12cm2 2nd reader 3,45cmx4,6=15,87cm3 T1 T2 RECIST = 4,6cm-4cm/4cm=0,15 i.e. SD (cutoff for PD ≥ 20%)

17. Higher cutoff for PD in RECIST 1.0 Assuminga spherical tumorvolume: • a 25% increase in the 2D cross-product is equal to a 40% increase in the 3D volume • a 20% 1D increase in the longest diameter is equal to a 44% 2D increase in the cross-product and to a 73% increase in 3D volume

18. Technological bias Hampers reliable longitudinal comparisons in clinical trials.

21. www.recist.com www.recist.com

34. Two major limitations of RECIST • Inter-observer variability • Different morphological behaviour of lesions when using targeted therapies.

36. Oxnard G, JCO Vol 29; 2011

37. Oxnard G, JCO Vol 29; 2011

41. Specialized software

42. Lesion Segmentation

43. Lesion Segmentation Pre Pre 123.6 mm3 Post Post 92.4 mm3

46. Patient report

49. Liver Analysis 49 Courtesy of Philips

50. Liver Analysis Courtesy of Philips