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
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
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
Biological Characterization
• Underlying concept for predictive assays
• Objective to guide rational therapeutic interventions
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
Problems with Lab-Based PAs
• Invasive
• Limited to accessible tumors
• Heterogeneity vs sample size
• Culture methods slow
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
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
Small Animal PETValidation Studies in Mice – F-18
Fluoride
18F fluoride PET bone scan of a mouse
Small Animal PETValidation Studies in Mice – F-18 FLT
F-18 fluorothymidine (FLT) for DNA synthesis
• Transgenic mouse model with spontaneous lymphoma
Small Animal PETValidation Studies in Mice - FET
• A431 xenograft in nude mouse
F-18 fluroethyltyrosine (FET) for amino-acid transport
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
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27
Day
Human Studies with Novel Tracers at Peter Mac
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
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
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
Tracers for PET Imaging of Hypoxia
• 2-nitroimidazole compounds 18F-MISO18F-EF518FAZA
• non-nitro compound 60Cu ATSM
• T3 N1 SCC base of tongue• Central uptake in viable tumor and in left cervical node
FDG
FAZA
Imaging for Hypoxia with FAZA
Comparison FAZA vs FMISO
• T4N0 SCC post pharyngeal wall
• Planned treatment with tirapazamine
p5500s0s2FAZA FMISO
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
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
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
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
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
T4 SCC palate and oropharynx
Outcome
Patient clinically, radiologically and metabolically free of disease 2 years post treatment, with good salivary function
Time to Loco-Regional Failure (n=122)
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% l
ocor
egio
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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
Failure-free Survival
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% 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
Overall Survival
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% 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
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
Hypoxia Imaging – F MISO
Hypoxia Imaging
FDG(Glucose)
F MISO(Hypoxia)
Carcinoma of larynx with hypoxic neck nodal mass
p1597s0s1
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
45 patients had baseline imaging of tumor hypoxia
with F-MISO
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
Time to Locoregional Failure by Treatment and Hypoxic Status
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TPZ / hypoxiccis5FU / oxicTPZ / oxiccis5FU / hypoxic
Utility of PET in Patients with
a Residual Structural
Abnormality following Radical
Treatment
Jul 97 T3 N3 SCC L tonsil, post incisional Bx neck node
Close-up neck
Aug 97 midway thru TPZ/RT
Dec 97 – residual induration, PET –ve; RND, path –ve
Therapeutic Monitoring
• Left base tongue primary with bulky bilateral upper deep cervical lymphadenopathy
• Clinical progression on treatment
Baseline Evaluation
4 weeks into treatment
p710
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
Sequential Clinical Response
Long lag between metabolic and clinical responseComplete local pathological response confirmed
p710
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
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
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%)
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%)
Survival by PET findings
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Esti
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d %
su
rviv
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0 1 2 3 4 5 6 7Years following PET scan
NegativeTotalPositive
(24)(49)(25)
P < 0.0001
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)
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
Patient population
• 39 patients median age 55 (37-89)– Male 29– Female 10
• Primary sites– Oropharynx 31– Larynx 5– Hypopharynx 3
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)
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
Treatment
• Chemo-radiotherapy 34– Chemoboost 22– TPZ/cisplat regimen 12
• Radiotherapy alone– Standard fractionation 1– Altered fractionation 4
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
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
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%
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
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
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
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
Therapeutic Monitoring
Does Metabolic Response Predict Survival in NSCLC?
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
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
Metabolic Response
Primary metabolic CR with associated radiation pneumonitis
Before chemo-RT 2 months post treatment
Complete Response: (Tumoral uptake=Mediastinal)
Partial Response
Persistent disease 14 weeks post RTCR post salvage surgery: Path confirmed viable tumor
Baseline study
PET Responses in 88 Patients
Scans performed median 70 days post RT
CR 40 (45%)
PR 32 (36%)
NR 5 (6%)
PD 11 (13%)
Survival by PET Response
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100E
stim
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tag
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urv
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0 6 12 18 24 30 36Months following PET scan
CRNo CR
(40)(48)
P = 0.0001
Survival by PET Response Grouped for Lung Radiotoxicity
Hicks et al, IJROBP, in press, 2003
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Esti
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su
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0 1 2 3 4Years following PET scan
CMR, no toxCMR, sig toxno CMR, sig toxno CMR, sig tox
(13)(21)(20)(19)
no
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
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
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