Download - Lester J Peters MD
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Use of PET to Biologically Characterize Tumors and Monitor Their Response to
Treatment
Juan A del Regato LectureStanford 2004
Lester J Peters MD
Peter MacCallum Cancer Centre
Melbourne, Australia
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Outline – Role of PET in:
• Biological characterization of tumors
• Therapeutic monitoring and guidance of post-treatment intervention
Illustrated by research at Peter MacCallum Cancer Centre in patients with advanced HNSCC and NSCLC
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History of PET facility at Peter MacCallum
– Director Rodney J Hicks MD
• 1996 Established with PENN-PET 300-H scanner – 18F FDG purchased
• 1998 Oxford cyclotron installed • 2001 GE Discovery PET/CT added
All patients entered into prospective relational data base
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Quarterly PET/FDG studies
Peter MacCallum Cancer Centre
Quarter
PE
T/F
DG
Stu
die
s
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Biological Characterization
• Underlying concept for predictive assays
• Objective to guide rational therapeutic interventions
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Lab-based Predictive Assays
Para-meter
Method Predictive value in reported studies
Clinical Utility
SF2 In vitro cell survival
most negative None
Tpot BUdR flow cytometry
most negative None
pO2 Eppendorf probe
most positive None
N In vitro plating efficiency
too few to assess None
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Problems with Lab-Based PAs
• Invasive
• Limited to accessible tumors
• Heterogeneity vs sample size
• Culture methods slow
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PET offers a New Approach to Biological Characterization
• Specific tracers now available for measurement of pO2 (FMiso, FAZA,
Cu ATSM), DNA (FLT) and protein (FET) synthesis rates
• Volume of metabolically active tumor (FDG) may be a surrogate for clonogen cell number
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The Allegretto Small-Animal (3D-GSO) PET scanner
Prototype devices for U Penn and Peter Mac in June 2003
PET for Translational Research
Small Animal Imaging
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Small Animal PETValidation Studies in Mice – F-18
Fluoride
18F fluoride PET bone scan of a mouse
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Small Animal PETValidation Studies in Mice – F-18 FLT
F-18 fluorothymidine (FLT) for DNA synthesis
• Transgenic mouse model with spontaneous lymphoma
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Small Animal PETValidation Studies in Mice - FET
• A431 xenograft in nude mouse
F-18 fluroethyltyrosine (FET) for amino-acid transport
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Small Animal PETValidation Studies in Mice - FAZA
• F-18 FAZA PET scan in a 20gm nude mouse with
A-431 xenograft
• Progressive growth of tumour associated with evidence of progressive central necrosis
20
24
27
Day
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Human Studies with Novel Tracers at Peter Mac
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Comparison of Metabolism and Proliferation
F-18 FDG F-18 FLT
• 1.5cm solitary nodule in the right lower lobe
• High risk biopsy due to poor lung function
• No mediastinal nodes on CT
• Assessment of suitability for “postage stamp” radiotherapy
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Comparison of Metabolism and Proliferation
F-18 FDG F-18 FLT
• Extensive right apical mass in young, non-smoker
• Mediastinal lymphadenopathy but negative FNA and bronchoscopy
• Subsequent positive serology for aspergillus
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Anti-Proliferative Response detected by FLT
p6098s2
p6098s1
• Metastatic malignant melanoma involving spleen, small bowel and retroperitoneal nodes
• Treated with anti-angiogenic compound (SU 11248) in Phase II trial
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Tracers for PET Imaging of Hypoxia
• 2-nitroimidazole compounds 18F-MISO18F-EF518FAZA
• non-nitro compound 60Cu ATSM
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• T3 N1 SCC base of tongue• Central uptake in viable tumor and in left cervical node
FDG
FAZA
Imaging for Hypoxia with FAZA
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Comparison FAZA vs FMISO
• T4N0 SCC post pharyngeal wall
• Planned treatment with tirapazamine
p5500s0s2FAZA FMISO
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Hypoxia Imaging in Tirapazamine Trials
Phase I PMCC patients only (n=16) all imaged with FMISO
Phase II TROG 98.02 (n=122) 45 patients from PMCC imaged with FMISO
Phase III HeadSTART (n=414/850)65 patients from PMCC imaged with FAZA
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TROG 98.02
•Arm 1 – Radiotherapy 70 Gy/ 7 wks with “Chemo-boost” cisplat +5FU
•Arm 2 – Radiotherapy 70 Gy/ 7 wks Arm 2 – Radiotherapy 70 Gy/ 7 wks with cisplat +tirapazaminewith cisplat +tirapazamine
Stage III or IVStage III or IVH&N SCCH&N SCC
13 13 institutions institutions
Stratify by Stratify by InstitutionInstitution
RRAANNDDOOMMIISSEE
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Tirapazamine/Cisplatin/Radiation Regimen
week 1 week 2 week 3 week 4 week 5 week
6 week 7
70 Gy in 35 fractions, 5/week
C+T C+T C+T
T T
C = Cisplatin 75 mg/m2
T = Tirapazamine, 290 mg/m2 with cis, 160 mg/m2 without cis
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Eligibility
• Stage III or IV (excluding T1N1) SCC head and neck
• No evidence of distant metastases• ECOG PS 0-2• Calculated creatinine clearance >
55ml/min• No prior chemotherapy or radiotherapy
for head and neck cancer
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Patient Characteristics (n=122)
cis/FU cis/TPZ
Median age 55 58
Stage IV 79% 83%
T4 and/or N3 45% 47%
ECOG 0,1,2 57,38,5 56,41,3
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T4 SCC palate and oropharynx
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Outcome
Patient clinically, radiologically and metabolically free of disease 2 years post treatment, with good salivary function
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Time to Loco-Regional Failure (n=122)
0
20
40
60
80
100
% l
ocor
egio
nal f
ailu
re-f
ree
0 1 2 3 4Years from randomisation
Cis+TPZCis+5FU
2P = 0.069.125 .25 .5 1 2 4
Hazard ratio 95% CI
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Failure-free Survival
0
20
40
60
80
100
% a
live
& f
ailu
re-f
ree
0 1 2 3 4Years from randomisation
Cis+TPZ
Cis+5FU
2P = 0.13
.25 .5 1 2 4Hazard ratio 95% CI
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Overall Survival
0
20
40
60
80
100
% s
urvi
ving
0 1 2 3 4Years from randomisation
Cis+TPZCis+5FU
2P = 0.28.25 .5 1 2 4
Hazard ratio 95% CI
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Differences from Stanford TrialPinto et al, ASCO 2003
• Patient populations – Stanford patients all resectable– Early surgery for non-responders
• Chemotherapy: TROG regimen– No induction therapy– More TPZ during RT– Front-end loading
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Hypoxia Imaging – F MISO
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Hypoxia Imaging
FDG(Glucose)
F MISO(Hypoxia)
Carcinoma of larynx with hypoxic neck nodal mass
p1597s0s1
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Therapeutic Outcome
Post-treatment FDG
p1597s5
• Complete metabolic response in non-hypoxic primary but poor metabolic response in hypoxic lymph node
•Persistent neck disease at surgery
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45 patients had baseline imaging of tumor hypoxia
with F-MISO
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Failure Pattern in F-MISO Scanned Patients
L-R Failure by Treatment
RT/Cis/FU RT/Cis/TPZ
Non-hypoxic 1/10 (2/3)
Hypoxic 8/13 1/19
Rischin et al, unpublished data, 2003
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Time to Locoregional Failure by Treatment and Hypoxic Status
0
20
40
60
80
100
% lo
core
gion
al f
ailu
re-f
ree
0 1 2 3 4Years from randomisation
TPZ / hypoxiccis5FU / oxicTPZ / oxiccis5FU / hypoxic
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Utility of PET in Patients with
a Residual Structural
Abnormality following Radical
Treatment
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Jul 97 T3 N3 SCC L tonsil, post incisional Bx neck node
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Close-up neck
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Aug 97 midway thru TPZ/RT
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Dec 97 – residual induration, PET –ve; RND, path –ve
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Therapeutic Monitoring
• Left base tongue primary with bulky bilateral upper deep cervical lymphadenopathy
• Clinical progression on treatment
Baseline Evaluation
4 weeks into treatment
p710
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Sequential Scans
Comparison of CT and PET responseEarly metabolic CRPartial, late CT response
p710
CT
F18-FDG PET
Baseline Mid-treatment End of Treatment Post Treatment Week 0 4 7 19 27 32
p710
CT
F18-FDG PET
Baseline Mid-treatment End of Treatment Post Treatment Week 0 4 7 19 27 32
p710
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Sequential Clinical Response
Long lag between metabolic and clinical responseComplete local pathological response confirmed
p710
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Post-treatment assessment
• Rate of regression of tumor masses after treatment is highly variable
• Residual metabolic activity in a treated cancer is much more significant than a residual mass
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Patients and Methods
• 53 HNSCC patients with a residual structural abnormality following definitive therapy
• Presence of active disease at index site or elsewhere assessed by conventional means (clinical + CT and/or MRI) +/- 18F FDG PET
• Accuracy assessed by pathology or observation of disease evolution (min FU 41 mths for pts alive at close-out date)
Ware et al, Head and Neck, in press, 2004
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Conventional Assessment vs PET in 44 Evaluable Patients
Both Conv and PET PET onlyConv onlyNeitherTotal accurate on PETTotal accurate on ConvPET +ve predictive valuePET -ve predictive value
Number correct1623 2 3391895% (CI 77%-100%)83% (CI 63%-95%)
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Impact of PET on Patient Management
• PET resulted in change of management plan in 21 pts (40%), majority being avoidance of planned salvage surgery
• Changed plan validated appropriate in 19/20 evaluable cases (95%)
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Survival by PET findings
0
20
40
60
80
100
Esti
mate
d %
su
rviv
ing
0 1 2 3 4 5 6 7Years following PET scan
NegativeTotalPositive
(24)(49)(25)
P < 0.0001
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Utility of PET to Obviate Planned Neck Dissection
• Standard practice to dissect necks of patients with primary CR, but residual palpable abnormality in the neck 6-8 wks after radical chemoRT
• Neck dissection is inappropriate if unnecessary (no viable residual) or futile (disease outside neck)
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Neck node study – Eligibility
• Node +ve Stage III-IV mucosal HNSCC treated definitively
• CR at primary site with residual palpable or CT/MRI neck mass ≥8 weeks after completion of treatment assessed by PET
• Pathologic confirmation or sufficient FU (>12 mths) to verify true neck status
Porceddu et al, Head and Neck in press, 2004
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Patient population
• 39 patients median age 55 (37-89)– Male 29– Female 10
• Primary sites– Oropharynx 31– Larynx 5– Hypopharynx 3
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PET scans
• Performed to guide neck management at median 12 (8-32) wks post treatment
• Objective of PET to detect residual viable tumor in neck and/or presence of distant disease
• Accuracy assessed by pathology or clinical evolution with median FU 39 mths (15-88 mths)
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T and N staging
T stage
N stage
1 2 3 4 Total
1 0 1 0 0 1
2a 1 5 3 0 9
2b 2 3 1 2 8
2c 0 3 7 1 11
3 3 6 0 1 10
Total 6 18 11 4 39
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Treatment
• Chemo-radiotherapy 34– Chemoboost 22– TPZ/cisplat regimen 12
• Radiotherapy alone– Standard fractionation 1– Altered fractionation 4
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Results (n=39)
• Initial neck stage:N1: 1 N2: 28 N3: 10
• Residual nodal size: 1.5 cm (0.8-3.5cm)• PET negative in 32 patients
27 observed 1 neck failure (P+N) 5 neck dissections All path negative
• PET positive in 7 patients 7 neck dissections 5 path positive
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Results (cont)
• Survival: 26 of 39 pts alive NED• Pattern of failure
– 2 loco-regional relapse (P+N)– 7 distant metastases– 2 metachronous lung primary– 2 unrelated causes – 0 isolated neck relapse
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Predictive value of PET
• 32 patients PET –ve in neck• 5 had neck dissection, all path –ve
• 27 observed with 1 failure (in primary site and neck)
31 true negative, 1 false negative
Negative predictive value 97%
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Explanatory hypothesis
• Repopulation occurs rapidly in H&N cancer (median time to clinical recurrence 6 mths)
• Clonal regeneration leads to nodular, rather than diffuse recurrence
• By 12 weeks, resolution of PET is sufficient to detect most recurrences
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Time frame important
• Scanning too soon after RT is less accurate
– Rogers et al (IJROBP 2004) reported 5 of 6
false negatives in patients scanned 4 weeks post treatment
– Kubota et al (EJNMMI 2004) reported 91% negative predictive value in 43 lesions in 36 patients scanned 4 months post treatment
– False positives also more likely soon after radiotherapy because of residual inflammatory reaction
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Outcomes in Peter Mac series
Patients imagedN=39
PET + N=7
PET – N=32
Neck DissectionN=5
Neck DissectionN=7
Path +N=5
Path +N=0
Path –N=5
ObservationN=27
Path –N=2
FailureNeck and Prim 1
Distant 2
Failure None
FailureDistant 1
Clinical FU34 (16-86) mths
FailureNeck and Prim 1
Distant 4
Failure None
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Current Peter Mac protocol
8 weeks Clinical Exam
12 weeks Clinical Exam
& CT/MRI
PET Scan
Observe#
Neck Dissection
Observe*
Selective Neck Dissection
Primary CR Neck NR or PD
Neck CR
PET +
PET -
Primary CR Neck PR
Node >1cm stable for ≥2
mths*Regular FU schedule
#Monthly until CR achieved
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Therapeutic Monitoring
Does Metabolic Response Predict Survival in NSCLC?
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Aims of Study
1) To study correlation between 18F FDG PET response and survival in NSCLC following radical (chemo) RT
2) To determine if PET can delineate a sub-group of patients who may benefit from additional therapy
Mac Manus et al, JCO 21:1285, 2003
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Metabolic Response Assessment
• Fused pre- and post-treatment PET scans displayed using SUV calibrated scale
• Uptake in irradiated lung beyond initial tumor volume assessed separately as measure of radiation pneumonitis
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Metabolic Response
Primary metabolic CR with associated radiation pneumonitis
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Before chemo-RT 2 months post treatment
Complete Response: (Tumoral uptake=Mediastinal)
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Partial Response
Persistent disease 14 weeks post RTCR post salvage surgery: Path confirmed viable tumor
Baseline study
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PET Responses in 88 Patients
Scans performed median 70 days post RT
CR 40 (45%)
PR 32 (36%)
NR 5 (6%)
PD 11 (13%)
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Survival by PET Response
0
20
40
60
80
100E
stim
ate
d p
erc
en
tag
e s
urv
ivin
g
0 6 12 18 24 30 36Months following PET scan
CRNo CR
(40)(48)
P = 0.0001
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Survival by PET Response Grouped for Lung Radiotoxicity
Hicks et al, IJROBP, in press, 2003
0
20
40
60
80
100
Esti
mate
d %
su
rviv
ing
0 1 2 3 4Years following PET scan
CMR, no toxCMR, sig toxno CMR, sig toxno CMR, sig tox
(13)(21)(20)(19)
no
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Conclusions – PET Response
• PET-response to radical RT/chemo RT separated patients into groups with widely differing survival probabilities
• Response less than CR associated with poor survival
• PET may identify patients suitable for salvage therapy
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Overall Conclusions
• FDG PET has established itself as having an invaluable role in radiation oncology
• New tracers permitting biological characterisation of tumors are becoming available
• Access to PET/CT imaging should be an integral part of modern radiation oncology practice
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Acknowledgements
Special thanks to colleagues at Peter Mac: • Rod Hicks, PET Centre Director• Rob Ware, PET Centre• Sandro Porceddu, H&N Unit• Michael Mac Manus, Lung Unit
for their help in preparing this lecture