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Radiology Radiology Radiology Radiology

Scott Schuetze, MD, PhDScott Schuetze, MD, PhD

University of MichiganUniversity of Michigan

Scott Schuetze, MD, PhDScott Schuetze, MD, PhD

University of MichiganUniversity of Michigan

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DisclosureDisclosureDisclosureDisclosureI am not a radiologistI am not a radiologistI am not a radiologistI am not a radiologist

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Utility of imagingUtility of imagingUtility of imagingUtility of imaging

Before diagnosisBefore diagnosisDuring stagingDuring stagingDuring treatmentDuring treatment

Before diagnosisBefore diagnosisDuring stagingDuring stagingDuring treatmentDuring treatment

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Advanced imaging is Advanced imaging is overused prior to referral to overused prior to referral to

a musculoskeletal oncologista musculoskeletal oncologist

Advanced imaging is Advanced imaging is overused prior to referral to overused prior to referral to

a musculoskeletal oncologista musculoskeletal oncologist

Drs. Miller, Avedian, Cummings, BalachDrs. Miller, Avedian, Cummings, Balach

Universities of Iowa, Arizona, Stanford, Universities of Iowa, Arizona, Stanford, Connecticut, & Virginia Mason (Seattle)Connecticut, & Virginia Mason (Seattle)

Drs. Miller, Avedian, Cummings, BalachDrs. Miller, Avedian, Cummings, Balach

Universities of Iowa, Arizona, Stanford, Universities of Iowa, Arizona, Stanford, Connecticut, & Virginia Mason (Seattle)Connecticut, & Virginia Mason (Seattle)

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What should the generalist What should the generalist or primary provider know?or primary provider know?

What should the generalist What should the generalist or primary provider know?or primary provider know?

What is appropriate imaging to evaluate What is appropriate imaging to evaluate complaint?complaint? PainPain MassMass

Imaging for bone vs soft tissue lesion?Imaging for bone vs soft tissue lesion?What information is necessary for the What information is necessary for the

specialist to accept the referral?specialist to accept the referral?

What is appropriate imaging to evaluate What is appropriate imaging to evaluate complaint?complaint? PainPain MassMass

Imaging for bone vs soft tissue lesion?Imaging for bone vs soft tissue lesion?What information is necessary for the What information is necessary for the

specialist to accept the referral?specialist to accept the referral?

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Study strengthsStudy strengthsStudy strengthsStudy strengths Geographic diversity – NW, NE, Geographic diversity – NW, NE,

California, South-west, Mid-west, TxCalifornia, South-west, Mid-west, Tx Inclusion of 8 centersInclusion of 8 centers Prospective consecutive case selection Prospective consecutive case selection Relatively large number of casesRelatively large number of cases Pre-defined criteria for imaging utilityPre-defined criteria for imaging utility Statistical analysisStatistical analysis

Geographic diversity – NW, NE, Geographic diversity – NW, NE, California, South-west, Mid-west, TxCalifornia, South-west, Mid-west, Tx

Inclusion of 8 centersInclusion of 8 centers Prospective consecutive case selection Prospective consecutive case selection Relatively large number of casesRelatively large number of cases Pre-defined criteria for imaging utilityPre-defined criteria for imaging utility Statistical analysisStatistical analysis

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Study limitationsStudy limitationsStudy limitationsStudy limitations U.S. perspectiveU.S. perspective Pre-defined criteria may be subjectivePre-defined criteria may be subjective Results for bone & soft tissue combinedResults for bone & soft tissue combined Sequencing of imaging not detailedSequencing of imaging not detailed Imaging may be driven local radiologists Imaging may be driven local radiologists

interpreting radiographs and/or MRI & interpreting radiographs and/or MRI & recommending additional studiesrecommending additional studies

U.S. perspectiveU.S. perspective Pre-defined criteria may be subjectivePre-defined criteria may be subjective Results for bone & soft tissue combinedResults for bone & soft tissue combined Sequencing of imaging not detailedSequencing of imaging not detailed Imaging may be driven local radiologists Imaging may be driven local radiologists

interpreting radiographs and/or MRI & interpreting radiographs and/or MRI & recommending additional studiesrecommending additional studies

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Study findingsStudy findingsStudy findingsStudy findings MRI useful in majority of soft tissue tumors, MRI useful in majority of soft tissue tumors,

unnecessary in bone lesionsunnecessary in bone lesions Geographic differences in CT frequency Geographic differences in CT frequency

(highest in TX, OK, SC)(highest in TX, OK, SC) Bone scanning and US were infrequentBone 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 Advanced imaging overused in benign

bone lesionsbone lesions

MRI useful in majority of soft tissue tumors, MRI useful in majority of soft tissue tumors, unnecessary in bone lesionsunnecessary in bone lesions

Geographic differences in CT frequency Geographic differences in CT frequency (highest in TX, OK, SC)(highest in TX, OK, SC)

Bone scanning and US were infrequentBone 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 Advanced imaging overused in benign

bone lesionsbone lesions

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Lessons learnedLessons learnedLessons learnedLessons learned

Orthopaedic surgeons as guilty as primary Orthopaedic surgeons as guilty as primary carecare

CT, bone scans, PET and US are frequently CT, bone scans, PET and US are frequently unnecessary for diagnosisunnecessary 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 Target orthopaedic surgeons, primary care

and/or radiologists?and/or radiologists?

Orthopaedic surgeons as guilty as primary Orthopaedic surgeons as guilty as primary carecare

CT, bone scans, PET and US are frequently CT, bone scans, PET and US are frequently unnecessary for diagnosisunnecessary 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 Target orthopaedic surgeons, primary care

and/or radiologists?and/or radiologists?

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Pre-referral take-awayPre-referral take-awayPre-referral take-awayPre-referral take-away

High quality MRI with contrast for High quality MRI with contrast for soft tissue masssoft tissue mass

Plain x-ray for bone lesionPlain x-ray for bone lesionLet the specialists sort out the restLet the specialists sort out the rest

High quality MRI with contrast for High quality MRI with contrast for soft tissue masssoft tissue mass

Plain x-ray for bone lesionPlain x-ray for bone lesionLet the specialists sort out the restLet the specialists sort out the rest

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Pulmonary micronodules do Pulmonary micronodules do not impact survival in young not impact survival in young

patientspatients

Pulmonary micronodules do Pulmonary micronodules do not impact survival in young not impact survival in young

patientspatients

Drs. Gitelis, Cipriano & KentDrs. Gitelis, Cipriano & Kent

Rush Medical CollegeRush Medical College

Drs. Gitelis, Cipriano & KentDrs. Gitelis, Cipriano & Kent

Rush Medical CollegeRush Medical College

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What is the clinical significance What is the clinical significance of <1 cm lung nodules on CT?of <1 cm lung nodules on CT?

What is the clinical significance What is the clinical significance of <1 cm lung nodules on CT?of <1 cm lung nodules on CT?

Patient demographics – age, Patient demographics – age, occupation, residence, inhalational occupation, residence, inhalational substance use/abusesubstance use/abuse

Medical historyMedical historySarcoma sub-typeSarcoma sub-typeNodule number and distributionNodule number and distributionSlice thickness of scanSlice thickness of scan

Patient demographics – age, Patient demographics – age, occupation, residence, inhalational occupation, residence, inhalational substance use/abusesubstance use/abuse

Medical historyMedical historySarcoma sub-typeSarcoma sub-typeNodule number and distributionNodule number and distributionSlice thickness of scanSlice thickness of scan

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Which nodules to worry over?Which nodules to worry over?Which nodules to worry over?Which nodules to worry over?19 yo Ewings

50 yo UPS

35 yo LMS

65 yo liposarc

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Which nodules to worry over?Which nodules to worry over?Which nodules to worry over?Which nodules to worry over?19 yo Ewings

50 yo UPS

35 yo LMS

65 yo liposarc

? LMS

Histoplasma MALT

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Study designStudy designStudy designStudy design 96 pt subset of 380 pts96 pt subset of 380 pts Age <50 yrs, bone and soft tissue sarcomaAge <50 yrs, bone and soft tissue sarcoma 80% received chemotherapy80% received chemotherapy Overall survival endpointOverall survival endpoint 4 strata4 strata

No lung nodules (47%)No lung nodules (47%) Single nodule <5 mm (26%)Single nodule <5 mm (26%) >1 nodule <5 mm (13%)>1 nodule <5 mm (13%) >>1 nodule 1 nodule >>5 mm (15%)5 mm (15%)

96 pt subset of 380 pts96 pt subset of 380 pts Age <50 yrs, bone and soft tissue sarcomaAge <50 yrs, bone and soft tissue sarcoma 80% received chemotherapy80% received chemotherapy Overall survival endpointOverall survival endpoint 4 strata4 strata

No lung nodules (47%)No lung nodules (47%) Single nodule <5 mm (26%)Single nodule <5 mm (26%) >1 nodule <5 mm (13%)>1 nodule <5 mm (13%) >>1 nodule 1 nodule >>5 mm (15%)5 mm (15%)

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Study resultsStudy resultsStudy resultsStudy results75% of nodules <5 mm and 100% of 75% of nodules <5 mm and 100% of

nodules nodules >>5 mm biopsied were sarcoma5 mm biopsied were sarcomaSurvival worse for patients with nodule Survival worse for patients with nodule

>>5 mm5 mm

75% of nodules <5 mm and 100% of 75% of nodules <5 mm and 100% of nodules nodules >>5 mm biopsied were sarcoma5 mm biopsied were sarcoma

Survival worse for patients with nodule Survival worse for patients with nodule >>5 mm5 mm

80%76%68%

36%

No difference between

Groups 1-3

p < 0.05 for Groups

1 - 3 compared to Group 4

Figure 1: Influence of Pulmonary Nodules at Presentation on Survival in Sarcoma Patients Under age 50.

(N = 96, Mean Follow up 47.2 Months)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 10 20 30 40 50 60 70 80 90 100 110

Surv

ival

Time from Diagnosis (months)

Group 1: No Nodules n = 45

Group 2: 1 Nodule < 5mm n = 25

Group 4: Any number of Nodules > 5mm n = 14

Group 3: Any number of Nodules < 5mm n = 37

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Related studiesRelated studiesRelated studiesRelated studies

Indeterminate Pulmonary Nodules in Patients with Sarcoma Affect SurvivalRissing S, Rougraff B, Davis KClinical Orthopaedics & Related Research459:118-121, 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 cancer 13 (32%) 15 (30%) 46 (59%)

Cancer 115 (42%) 103 (69%) 77 (84%)

426 pts with nodules

Pulmonary nodules resected at VATS: etiology in 426 patientsGinsberg MS, Griff SK, Go BD, et al.Radiology 213:227-82, 1999

Nodule size at 1st CT

<5 mm >5 mm

benign 15 (60%) 7 (27%)

metastasis 10 (40%) 19 (73%)

51 pts with osteosarcoma

CT of pulmonary metastases from osteosarcoma: the less poor techniquePicci P, Vanel D, Briccoli A, et al.Ann Oncol 12:1601-04, 2001

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Informal survey results – basis Informal survey results – basis for nodules as metastatic diseasefor nodules as metastatic diseaseInformal survey results – basis Informal survey results – basis

for nodules as metastatic diseasefor nodules as metastatic disease Ewing AEWS0031: 1 nodule >1 cm or >1 Ewing AEWS0031: 1 nodule >1 cm or >1

nodules >0.5 cmnodules >0.5 cm EURAMOS-1: 1 nodule EURAMOS-1: 1 nodule >>1 cm or 1 cm or >>3 nodules 3 nodules

>>0.5 cm0.5 cm COG ARST: 1 nodule COG ARST: 1 nodule >>1 cm1 cm French trials: 1 nodule >1 cmFrench trials: 1 nodule >1 cm Italian trials: 1 nodule >0.5 cmItalian trials: 1 nodule >0.5 cm SARC012: the oncologist, radiologist and SARC012: the oncologist, radiologist and

surgeon should use best judgmentsurgeon should use best judgment

Ewing AEWS0031: 1 nodule >1 cm or >1 Ewing AEWS0031: 1 nodule >1 cm or >1 nodules >0.5 cmnodules >0.5 cm

EURAMOS-1: 1 nodule EURAMOS-1: 1 nodule >>1 cm or 1 cm or >>3 nodules 3 nodules >>0.5 cm0.5 cm

COG ARST: 1 nodule COG ARST: 1 nodule >>1 cm1 cm French trials: 1 nodule >1 cmFrench trials: 1 nodule >1 cm Italian trials: 1 nodule >0.5 cmItalian trials: 1 nodule >0.5 cm SARC012: the oncologist, radiologist and SARC012: the oncologist, radiologist and

surgeon should use best judgmentsurgeon should use best judgment

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ConclusionsConclusionsConclusionsConclusions

Metastasis (<5 mm) at diagnosis does not Metastasis (<5 mm) at diagnosis does not = poor outcome= poor outcome

Lung nodules Lung nodules >>5 mm should raise 5 mm should raise suspicionsuspicion

Many lung nodules should raise suspicionMany lung nodules should raise suspicionStandardize criteria for clinical trials?Standardize criteria for clinical trials?Treat for cure!Treat for cure!

Metastasis (<5 mm) at diagnosis does not Metastasis (<5 mm) at diagnosis does not = poor outcome= poor outcome

Lung nodules Lung nodules >>5 mm should raise 5 mm should raise suspicionsuspicion

Many lung nodules should raise suspicionMany lung nodules should raise suspicionStandardize criteria for clinical trials?Standardize criteria for clinical trials?Treat for cure!Treat for cure!

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Total lesion glycolysis by Total lesion glycolysis by FDG-PET is of predictive FDG-PET is of predictive

value in soft tissue sarcomavalue in soft tissue sarcoma

Total lesion glycolysis by Total lesion glycolysis by FDG-PET is of predictive FDG-PET is of predictive

value in soft tissue sarcomavalue in soft tissue sarcoma

Drs. Choi, Ha, Cho, Kang, Kim, Drs. Choi, Ha, Cho, Kang, Kim, Pang & HanPang & Han

Seoul National University HospitalSeoul National University Hospital

Drs. Choi, Ha, Cho, Kang, Kim, Drs. Choi, Ha, Cho, Kang, Kim, Pang & HanPang & Han

Seoul National University HospitalSeoul National University Hospital

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Potential value of dynamic Potential value of dynamic imaging in sarcomaimaging in sarcoma

Potential value of dynamic Potential value of dynamic imaging in sarcomaimaging in sarcoma

Prognostic information: natural Prognostic information: natural course of diseasecourse of disease

Predictive information: disease Predictive information: disease response to interventionresponse to intervention

Prognostic information: natural Prognostic information: natural course of diseasecourse of disease

Predictive information: disease Predictive information: disease response to interventionresponse to intervention

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FDG PET semi-quantitative FDG PET semi-quantitative measurementsmeasurements

FDG PET semi-quantitative FDG PET semi-quantitative measurementsmeasurements

SUVSUVmaxmax: maximum pixel value w/i slice with highest FDG : maximum pixel value w/i slice with highest FDG uptakeuptake

SUVSUVpeakpeak: average pixel value w/i fixed ROI in area with : average pixel value w/i fixed ROI in area with highest FDG uptakehighest FDG uptake

SUVSUVaveave: average pixel value w/i tumor ROI: average pixel value w/i tumor ROI TBR: average value w/i tumor ROI / average value w/i TBR: average value w/i tumor ROI / average value w/i

blood poolblood pool TLG: SUVTLG: SUVaveave of uptake above minimum threshold x TV of uptake above minimum threshold x TV MTV: volume of tumor within ROI in which FDG uptake is MTV: volume of tumor within ROI in which FDG uptake is

>40% of SUV>40% of SUVmaxmax

SUVSUVmaxmax: maximum pixel value w/i slice with highest FDG : maximum pixel value w/i slice with highest FDG uptakeuptake

SUVSUVpeakpeak: average pixel value w/i fixed ROI in area with : average pixel value w/i fixed ROI in area with highest FDG uptakehighest FDG uptake

SUVSUVaveave: average pixel value w/i tumor ROI: average pixel value w/i tumor ROI TBR: average value w/i tumor ROI / average value w/i TBR: average value w/i tumor ROI / average value w/i

blood poolblood pool TLG: SUVTLG: SUVaveave of uptake above minimum threshold x TV of uptake above minimum threshold x TV MTV: volume of tumor within ROI in which FDG uptake is MTV: volume of tumor within ROI in which FDG uptake is

>40% of SUV>40% of SUVmaxmax

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Challenges in Challenges in standardizationstandardizationChallenges in Challenges in

standardizationstandardization

Dynamic versus static measurementsDynamic versus static measurementsFDG administration protocolFDG administration protocolHardware calibrationHardware calibrationObserver dependent ROIObserver dependent ROIDefinitionsDefinitions

Dynamic versus static measurementsDynamic versus static measurementsFDG administration protocolFDG administration protocolHardware calibrationHardware calibrationObserver dependent ROIObserver dependent ROIDefinitionsDefinitions

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FDG PET and sarcoma FDG PET and sarcoma prognosisprognosis

FDG PET and sarcoma FDG PET and sarcoma prognosisprognosis

Recurrence-free survival

Factor Disease HR 95% CI P value

SUVmax >6 STS 3.2 1.3-8.2 0.015

SUVmax >6 EWS 0.47

SUVmax >6 OS 0.41

SUVmax >15 OS 4.5 1.3-15.3 0.015

SUVmax does not account for tumor heterogeneitySUVmax does not account for tumor heterogeneity Do other parameters improve prognostic information?Do other parameters improve prognostic information?

SUVmax does not account for tumor heterogeneitySUVmax does not account for tumor heterogeneity Do other parameters improve prognostic information?Do other parameters improve prognostic information?

Schuetze S et al. 2005, Cancer 103:339Hawkins D et al. 2009, Cancer 115:3519Hawkins D et al. 2005, JCO 23:8828.Costelloe C et al, 2009, J Nuc Med 50:340.

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Study dataStudy dataStudy dataStudy data 66 pts with STS66 pts with STS RetrospectiveRetrospective AJCC stageAJCC stage

I: 16%I: 16% II: 24%II: 24% III: 46%III: 46% IV: 14%IV: 14%

Adjuvant txAdjuvant tx Radiotherapy: 47%Radiotherapy: 47% Chemotherapy: 29%Chemotherapy: 29%

66 pts with STS66 pts with STS RetrospectiveRetrospective AJCC stageAJCC stage

I: 16%I: 16% II: 24%II: 24% III: 46%III: 46% IV: 14%IV: 14%

Adjuvant txAdjuvant tx Radiotherapy: 47%Radiotherapy: 47% Chemotherapy: 29%Chemotherapy: 29% SUVmax: 6

TLG: 250MTV: 40 cm3

Receiver operating characteristics

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K-M analysis of sarcoma K-M analysis of sarcoma FDG metabolismFDG metabolism

K-M analysis of sarcoma K-M analysis of sarcoma FDG metabolismFDG metabolism

Choi E-S et al. 2013, Eur J Nucl Med Mol Imaging DOI 10.1007/s00259-013-2511-y

P<0.001 P=0.022 P=0.031

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Multivariate analysis factors Multivariate analysis factors affecting PFSaffecting PFS

Multivariate analysis factors Multivariate analysis factors affecting PFSaffecting PFS

Factor Value Univariate Multivariate

P value RR 95% CI P value

AJCC stage III or IV 0.035 3.36 1.01-11.02 0.047

Metastases Present <0.001 5.99 1.81-19.8 0.003

TLG 250 0.001 4.79 1.51-15.23 0.008

SUVmax 6 0.031 0.203

MTV 40 cm3 0.022 0.736

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Multivariate analysis factors Multivariate analysis factors affecting PFSaffecting PFS

Multivariate analysis factors Multivariate analysis factors affecting PFSaffecting PFS

Factor Value Univariate Multivariate

P value RR 95% CI P value

AJCC stage III or IV 0.035 3.36 1.01-11.02 0.047

Metastases Present <0.001 5.99 1.81-19.8 0.003

TLG 250 0.001 4.79 1.51-15.23 0.008

SUVmax 6 0.031 0.203

MTV 40 cm3 0.022 0.736

Is TLG predictive of response to therapy ina uniformly treated high-risk population?

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FDG PET in sarcomaFDG PET in sarcomaFDG PET in sarcomaFDG PET in sarcoma Potential roles in sarcoma managementPotential roles in sarcoma management

Prognostic information / risk of relapsePrognostic information / risk of relapse Predict response to adjuvant therapyPredict response to adjuvant therapy Early marker of response to drug therapyEarly marker of response to drug therapy

Foundation of single-institutional experience Foundation of single-institutional experience (variability minimized)(variability minimized)

Need more experience in multi-site trials Need more experience in multi-site trials (more variability)(more variability)

Potential roles in sarcoma managementPotential roles in sarcoma management Prognostic information / risk of relapsePrognostic information / risk of relapse Predict response to adjuvant therapyPredict response to adjuvant therapy Early marker of response to drug therapyEarly marker of response to drug therapy

Foundation of single-institutional experience Foundation of single-institutional experience (variability minimized)(variability minimized)

Need more experience in multi-site trials Need more experience in multi-site trials (more variability)(more variability)

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Thanks to the presenters & Thanks to the presenters & session chairssession chairs

Thanks to the presenters & Thanks to the presenters & session chairssession chairs