1. 1 RadiologyRadiology Scott Schuetze, MD, PhD University of Michigan Scott Schuetze, MD, PhD University of Michigan

2. 2 DisclosureDisclosure I am not a radiologist I am not a radiologist

3. 3 Utility of imaging Before diagnosis Before diagnosis During staging During staging During treatment During treatment Before diagnosis Before diagnosis During staging During staging During treatment During treatment

4. 4 Advanced imaging is overused prior to referral to a musculoskeletal oncologist Drs. Miller, Avedian, Cummings, Balach Universities of Iowa, Arizona, Stanford, Connecticut, & Virginia Mason (Seattle) Drs. Miller, Avedian, Cummings, Balach Universities of Iowa, Arizona, Stanford, Connecticut, & Virginia Mason (Seattle)

5. 5 What should the generalist or primary provider know? What is appropriate imaging to evaluate complaint? What is appropriate imaging to evaluate complaint? Pain Pain Mass Mass Imaging for bone vs soft tissue lesion? Imaging for bone vs soft tissue lesion? What information is necessary for the specialist to accept the referral? What information is necessary for the specialist to accept the referral? What is appropriate imaging to evaluate complaint? What is appropriate imaging to evaluate complaint? Pain Pain Mass Mass Imaging for bone vs soft tissue lesion? Imaging for bone vs soft tissue lesion? What information is necessary for the specialist to accept the referral? What information is necessary for the specialist to accept the referral?

6. 6 Study strengths Geographic diversity – NW, NE, California, South-west, Mid-west, Tx Geographic diversity – NW, NE, California, South-west, Mid-west, Tx Inclusion of 8 centers Inclusion of 8 centers Prospective consecutive case selection Prospective consecutive case selection Relatively large number of cases Relatively large number of cases Pre-defined criteria for imaging utility Pre-defined criteria for imaging utility Statistical analysis Statistical analysis Geographic diversity – NW, NE, California, South-west, Mid-west, Tx Geographic diversity – NW, NE, California, South-west, Mid-west, Tx Inclusion of 8 centers Inclusion of 8 centers Prospective consecutive case selection Prospective consecutive case selection Relatively large number of cases Relatively large number of cases Pre-defined criteria for imaging utility Pre-defined criteria for imaging utility Statistical analysis Statistical analysis

7. 7 Study limitations U.S. perspective U.S. perspective Pre-defined criteria may be subjective Pre-defined criteria may be subjective Results for bone & soft tissue combined Results for bone & soft tissue combined Sequencing of imaging not detailed Sequencing of imaging not detailed Imaging may be driven local radiologists interpreting radiographs and/or MRI & recommending additional studies Imaging may be driven local radiologists interpreting radiographs and/or MRI & recommending additional studies U.S. perspective U.S. perspective Pre-defined criteria may be subjective Pre-defined criteria may be subjective Results for bone & soft tissue combined Results for bone & soft tissue combined Sequencing of imaging not detailed Sequencing of imaging not detailed Imaging may be driven local radiologists interpreting radiographs and/or MRI & recommending additional studies Imaging may be driven local radiologists interpreting radiographs and/or MRI & recommending additional studies

8. 8 Study findings MRI useful in majority of soft tissue tumors, unnecessary in bone lesions MRI useful in majority of soft tissue tumors, unnecessary in bone lesions Geographic differences in CT frequency (highest in TX, OK, SC) Geographic differences in CT frequency (highest in TX, OK, SC) Bone scanning and US were infrequent Bone scanning and US were infrequent PET overused in OK (12%) vs Seattle (0%) PET overused in OK (12%) vs Seattle (0%) Advanced imaging overused in benign bone lesions Advanced imaging overused in benign bone lesions MRI useful in majority of soft tissue tumors, unnecessary in bone lesions MRI useful in majority of soft tissue tumors, unnecessary in bone lesions Geographic differences in CT frequency (highest in TX, OK, SC) Geographic differences in CT frequency (highest in TX, OK, SC) Bone scanning and US were infrequent Bone scanning and US were infrequent PET overused in OK (12%) vs Seattle (0%) PET overused in OK (12%) vs Seattle (0%) Advanced imaging overused in benign bone lesions Advanced imaging overused in benign bone lesions

9. 9 Lessons learned Orthopaedic surgeons as guilty as primary care Orthopaedic surgeons as guilty as primary care CT, bone scans, PET and US are frequently unnecessary for diagnosis CT, bone scans, PET and US are frequently unnecessary for diagnosis Opportunities for regional education? Opportunities for regional education? Opportunities for education during training? Opportunities for education during training? Target orthopaedic surgeons, primary care and/or radiologists? Target orthopaedic surgeons, primary care and/or radiologists? Orthopaedic surgeons as guilty as primary care Orthopaedic surgeons as guilty as primary care CT, bone scans, PET and US are frequently unnecessary for diagnosis CT, bone scans, PET and US are frequently unnecessary for diagnosis Opportunities for regional education? Opportunities for regional education? Opportunities for education during training? Opportunities for education during training? Target orthopaedic surgeons, primary care and/or radiologists? Target orthopaedic surgeons, primary care and/or radiologists?

10. 10 Pre-referral take-away High quality MRI with contrast for soft tissue mass High quality MRI with contrast for soft tissue mass Plain x-ray for bone lesion Plain x-ray for bone lesion Let the specialists sort out the rest Let the specialists sort out the rest High quality MRI with contrast for soft tissue mass High quality MRI with contrast for soft tissue mass Plain x-ray for bone lesion Plain x-ray for bone lesion Let the specialists sort out the rest Let the specialists sort out the rest

11. 11 Pulmonary micronodules do not impact survival in young patients Drs. Gitelis, Cipriano & Kent Rush Medical College Drs. Gitelis, Cipriano & Kent Rush Medical College

12. 12 What is the clinical significance of <1 cm lung nodules on CT? Patient demographics – age, occupation, residence, inhalational substance use/abuse Patient demographics – age, occupation, residence, inhalational substance use/abuse Medical history Medical history Sarcoma sub-type Sarcoma sub-type Nodule number and distribution Nodule number and distribution Slice thickness of scan Slice thickness of scan Patient demographics – age, occupation, residence, inhalational substance use/abuse Patient demographics – age, occupation, residence, inhalational substance use/abuse Medical history Medical history Sarcoma sub-type Sarcoma sub-type Nodule number and distribution Nodule number and distribution Slice thickness of scan Slice thickness of scan

13. 13 Which nodules to worry over? 19 yo Ewings 50 yo UPS 35 yo LMS 65 yo liposarc

14. 14 Which nodules to worry over? 19 yo Ewings 50 yo UPS 35 yo LMS 65 yo liposarc ?LMS HistoplasmaMALT

15. 15 Study design 96 pt subset of 380 pts 96 pt subset of 380 pts Age <50 yrs, bone and soft tissue sarcoma Age <50 yrs, bone and soft tissue sarcoma 80% received chemotherapy 80% received chemotherapy Overall survival endpoint Overall survival endpoint 4 strata 4 strata No lung nodules (47%) No lung nodules (47%) Single nodule <5 mm (26%) Single nodule <5 mm (26%) >1 nodule 1 nodule <5 mm (13%) >1 nodule >5 mm (15%) >1 nodule >5 mm (15%) 96 pt subset of 380 pts 96 pt subset of 380 pts Age <50 yrs, bone and soft tissue sarcoma Age <50 yrs, bone and soft tissue sarcoma 80% received chemotherapy 80% received chemotherapy Overall survival endpoint Overall survival endpoint 4 strata 4 strata No lung nodules (47%) No lung nodules (47%) Single nodule <5 mm (26%) Single nodule <5 mm (26%) >1 nodule 1 nodule <5 mm (13%) >1 nodule >5 mm (15%) >1 nodule >5 mm (15%)

16. 16 Study results 75% of nodules 5 mm biopsied were sarcoma 75% of nodules 5 mm biopsied were sarcoma Survival worse for patients with nodule >5 mm Survival worse for patients with nodule >5 mm 75% of nodules 5 mm biopsied were sarcoma 75% of nodules 5 mm biopsied were sarcoma Survival worse for patients with nodule >5 mm Survival worse for patients with nodule >5 mm

17. 17 Related studies Indeterminate Pulmonary Nodules in Patients with Sarcoma Affect Survival Rissing S, Rougraff B, Davis K Clinical Orthopaedics & Related Research 459:118-121, June 2007 71 sarcoma pts <1cm nodules # of malignant nodules Patient group <5 cm (n=128) >5 - <1 cm (n=118) >1 - <3 cm (n=123) No cancer13 (32%)15 (30%)46 (59%) Cancer115 (42%)103 (69%)77 (84%) 426 pts with nodules Pulmonary nodules resected at VATS: etiology in 426 patients Ginsberg MS, Griff SK, Go BD, et al. Radiology 213:227-82, 1999 Nodule size at 1 st CT <5 mm>5 mm benign15 (60%)7 (27%) metastasis10 (40%)19 (73%) 51 pts with osteosarcoma CT of pulmonary metastases from osteosarcoma: the less poor technique Picci P, Vanel D, Briccoli A, et al. Ann Oncol 12:1601-04, 2001

18. 18 Informal survey results – basis for nodules as metastatic disease Ewing AEWS0031: 1 nodule >1 cm or >1 nodules >0.5 cm Ewing AEWS0031: 1 nodule >1 cm or >1 nodules >0.5 cm EURAMOS-1: 1 nodule >1 cm or >3 nodules >0.5 cm EURAMOS-1: 1 nodule >1 cm or >3 nodules >0.5 cm COG ARST: 1 nodule >1 cm COG ARST: 1 nodule >1 cm French trials: 1 nodule >1 cm French trials: 1 nodule >1 cm Italian trials: 1 nodule >0.5 cm Italian trials: 1 nodule >0.5 cm SARC012: the oncologist, radiologist and surgeon should use best judgment SARC012: the oncologist, radiologist and surgeon should use best judgment Ewing AEWS0031: 1 nodule >1 cm or >1 nodules >0.5 cm Ewing AEWS0031: 1 nodule >1 cm or >1 nodules >0.5 cm EURAMOS-1: 1 nodule >1 cm or >3 nodules >0.5 cm EURAMOS-1: 1 nodule >1 cm or >3 nodules >0.5 cm COG ARST: 1 nodule >1 cm COG ARST: 1 nodule >1 cm French trials: 1 nodule >1 cm French trials: 1 nodule >1 cm Italian trials: 1 nodule >0.5 cm Italian trials: 1 nodule >0.5 cm SARC012: the oncologist, radiologist and surgeon should use best judgment SARC012: the oncologist, radiologist and surgeon should use best judgment

19. 19 ConclusionsConclusions Metastasis (<5 mm) at diagnosis does not = poor outcome Metastasis (<5 mm) at diagnosis does not = poor outcome Lung nodules >5 mm should raise suspicion Lung nodules >5 mm should raise suspicion Many lung nodules should raise suspicion Many lung nodules should raise suspicion Standardize criteria for clinical trials? Standardize criteria for clinical trials? Treat for cure! Treat for cure! Metastasis (<5 mm) at diagnosis does not = poor outcome Metastasis (<5 mm) at diagnosis does not = poor outcome Lung nodules >5 mm should raise suspicion Lung nodules >5 mm should raise suspicion Many lung nodules should raise suspicion Many lung nodules should raise suspicion Standardize criteria for clinical trials? Standardize criteria for clinical trials? Treat for cure! Treat for cure!

20. 20 Total lesion glycolysis by FDG-PET is of predictive value in soft tissue sarcoma Drs. Choi, Ha, Cho, Kang, Kim, Pang & Han Seoul National University Hospital Drs. Choi, Ha, Cho, Kang, Kim, Pang & Han Seoul National University Hospital

21. 21 Potential value of dynamic imaging in sarcoma Prognostic information: natural course of disease Prognostic information: natural course of disease Predictive information: disease response to intervention Predictive information: disease response to intervention Prognostic information: natural course of disease Prognostic information: natural course of disease Predictive information: disease response to intervention Predictive information: disease response to intervention

22. 22 FDG PET semi-quantitative measurements SUV max : maximum pixel value w/i slice with highest FDG uptake SUV max : maximum pixel value w/i slice with highest FDG uptake SUV peak : average pixel value w/i fixed ROI in area with highest FDG uptake SUV peak : average pixel value w/i fixed ROI in area with highest FDG uptake SUV ave : average pixel value w/i tumor ROI SUV ave : average pixel value w/i tumor ROI TBR: average value w/i tumor ROI / average value w/i blood pool TBR: average value w/i tumor ROI / average value w/i blood pool TLG: SUV ave of uptake above minimum threshold x TV TLG: SUV ave of uptake above minimum threshold x TV MTV: volume of tumor within ROI in which FDG uptake is >40% of SUV max MTV: volume of tumor within ROI in which FDG uptake is >40% of SUV max SUV max : maximum pixel value w/i slice with highest FDG uptake SUV max : maximum pixel value w/i slice with highest FDG uptake SUV peak : average pixel value w/i fixed ROI in area with highest FDG uptake SUV peak : average pixel value w/i fixed ROI in area with highest FDG uptake SUV ave : average pixel value w/i tumor ROI SUV ave : average pixel value w/i tumor ROI TBR: average value w/i tumor ROI / average value w/i blood pool TBR: average value w/i tumor ROI / average value w/i blood pool TLG: SUV ave of uptake above minimum threshold x TV TLG: SUV ave of uptake above minimum threshold x TV MTV: volume of tumor within ROI in which FDG uptake is >40% of SUV max MTV: volume of tumor within ROI in which FDG uptake is >40% of SUV max

23. 23 Challenges in standardization Dynamic versus static measurements Dynamic versus static measurements FDG administration protocol FDG administration protocol Hardware calibration Hardware calibration Observer dependent ROI Observer dependent ROI Definitions Definitions Dynamic versus static measurements Dynamic versus static measurements FDG administration protocol FDG administration protocol Hardware calibration Hardware calibration Observer dependent ROI Observer dependent ROI Definitions Definitions

24. 24 FDG PET and sarcoma prognosis Recurrence-free survival FactorDiseaseHR95% CIP value SUVmax >6STS3.21.3-8.20.015 SUVmax >6EWS0.47 SUVmax >6OS0.41 SUVmax >15OS4.51.3-15.30.015 SUVmax does not account for tumor heterogeneity SUVmax does not account for tumor heterogeneity Do other parameters improve prognostic information? Do other parameters improve prognostic information? Schuetze S et al. 2005, Cancer 103:339 Hawkins D et al. 2009, Cancer 115:3519 Hawkins D et al. 2005, JCO 23:8828. Costelloe C et al, 2009, J Nuc Med 50:340.

25. 25 Study data 66 pts with STS 66 pts with STS Retrospective Retrospective AJCC stage AJCC stage I: 16% I: 16% II: 24% II: 24% III: 46% III: 46% IV: 14% IV: 14% Adjuvant tx Adjuvant tx Radiotherapy: 47% Radiotherapy: 47% Chemotherapy: 29% Chemotherapy: 29% 66 pts with STS 66 pts with STS Retrospective Retrospective AJCC stage AJCC stage I: 16% I: 16% II: 24% II: 24% III: 46% III: 46% IV: 14% IV: 14% Adjuvant tx Adjuvant tx Radiotherapy: 47% Radiotherapy: 47% Chemotherapy: 29% Chemotherapy: 29% SUVmax: 6 TLG: 250 MTV: 40 cm 3 Receiver operating characteristics

26. 26 K-M analysis of sarcoma FDG metabolism Choi E-S et al. 2013, Eur J Nucl Med Mol Imaging DOI 10.1007/s00259-013-2511-y P<0.001P=0.022P=0.031

27. 27 Multivariate analysis factors affecting PFS FactorValueUnivariateMultivariate P valueRR95% CIP value AJCC stageIII or IV0.0353.361.01-11.020.047 MetastasesPresent<0.0015.991.81-19.80.003 TLG2500.0014.791.51-15.230.008 SUVmax60.0310.203 MTV40 cm 3 0.0220.736

28. 28 Multivariate analysis factors affecting PFS FactorValueUnivariateMultivariate P valueRR95% CIP value AJCC stageIII or IV0.0353.361.01-11.020.047 MetastasesPresent<0.0015.991.81-19.80.003 TLG2500.0014.791.51-15.230.008 SUVmax60.0310.203 MTV40 cm 3 0.0220.736 Is TLG predictive of response to therapy in a uniformly treated high-risk population?

29. 29 FDG PET in sarcoma Potential roles in sarcoma management Potential roles in sarcoma management Prognostic information / risk of relapse Prognostic information / risk of relapse Predict response to adjuvant therapy Predict response to adjuvant therapy Early marker of response to drug therapy Early marker of response to drug therapy Foundation of single-institutional experience (variability minimized) Foundation of single-institutional experience (variability minimized) Need more experience in multi-site trials (more variability) Need more experience in multi-site trials (more variability) Potential roles in sarcoma management Potential roles in sarcoma management Prognostic information / risk of relapse Prognostic information / risk of relapse Predict response to adjuvant therapy Predict response to adjuvant therapy Early marker of response to drug therapy Early marker of response to drug therapy Foundation of single-institutional experience (variability minimized) Foundation of single-institutional experience (variability minimized) Need more experience in multi-site trials (more variability) Need more experience in multi-site trials (more variability)

30. 30 Thanks to the presenters & session chairs