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

0

100

200

300

400

500

600

700

800

900

1996.3

1996.4

1997.1

1997.2

1997.3

1997.4

1998.1

1998.2

1998.3

1998.4

1999.1

1999.2

1999.3

1999.4

2000.1

2000.2

2000.3

2000.4

2001.1

2001.2

2001.3

2001.4

2002.1

2002.2

2002.3

2002.4

2003.1

2003.2

2003.3

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

20

24

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)

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

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

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

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

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

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

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

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

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

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

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