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Lester J Peters MD. Use of PET to Biologically Characterize Tumors and Monitor Their Response to Treatment Juan A del Regato Lecture Stanford 2004. Peter MacCallum Cancer Centre Melbourne, Australia. Outline – Role of PET in:. Biological characterization of tumors

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Lester J Peters MD

Use of PET to Biologically Characterize Tumors and Monitor Their Response to TreatmentJuan A del Regato LectureStanford 2004

Peter MacCallum Cancer Centre

Melbourne, Australia


Outline role of pet in
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
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


Quarterly PET/FDG studies

Peter MacCallum Cancer Centre

PET/FDG Studies

Quarter


Biological characterization
Biological Characterization

  • Underlying concept for predictive assays

  • Objective to guide rational therapeutic interventions



Problems with lab based pas
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
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


PET for Translational Research

Small Animal Imaging

The Allegretto Small-Animal (3D-GSO) PET scanner

Prototype devices for U Penn and Peter Mac in June 2003


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 pet validation studies in mice fet
Small Animal PETValidation Studies in Mice - FET

A431 xenograft in nude mouse

F-18 fluroethyltyrosine (FET) for amino-acid transport


Small animal pet validation studies in mice faza
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

Day

20

24

27



Comparison of Metabolism and Proliferation

  • 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

F-18 FDG

F-18 FLT


Comparison of Metabolism and Proliferation

  • Extensive right apical mass in young, non-smoker

  • Mediastinal lymphadenopathy but negative FNA and bronchoscopy

  • Subsequent positive serology for aspergillus

F-18 FDG

F-18 FLT


Anti-Proliferative Response detected by FLT

  • Metastatic malignant melanoma involving spleen, small bowel and retroperitoneal nodes

  • Treated with anti-angiogenic compound (SU 11248) in Phase II trial

p6098s1

p6098s2


Tracers for pet imaging of hypoxia
Tracers for PET Imaging of Hypoxia

  • 2-nitroimidazole compounds

    18F-MISO

    18F-EF5

    18FAZA

  • non-nitro compound

    60Cu ATSM


Imaging for Hypoxia with FAZA

FDG

FAZA

  • T3 N1 SCC base of tongue

  • Central uptake in viable tumor and in left cervical node


Comparison FAZA vs FMISO

  • T4N0 SCC post pharyngeal wall

  • Planned treatment with tirapazamine

p5500s0s2

FAZA FMISO


Hypoxia imaging in tirapazamine trials
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

TROG 98.02

Stage III or IV

H&N SCC

13 institutions

Stratify by

Institution

R

A

N

D

O

M

I

S

E


Tirapazamine cisplatin radiation regimen
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
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




Outcome
Outcome

Patient clinically, radiologically and metabolically free of disease 2 years post treatment, with good salivary function





Differences from stanford trial pinto et al asco 2003
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

FDG

(Glucose)

F MISO

(Hypoxia)

Carcinoma of larynx with hypoxic neck nodal mass

p1597s0s1


Therapeutic Outcome

  • Complete metabolic response in non-hypoxic primary but poor metabolic response in hypoxic lymph node

  • Persistent neck disease at surgery

p1597s5

Post-treatment FDG



Failure pattern in f miso scanned patients
Failure Pattern in F-MISO Scanned Patients F-MISO

Rischin et al, unpublished data, 2003



Utility of pet in patients with a residual structural abnormality following radical treatment
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 Abnormality following Radical Treatment


Close-up neck Abnormality following Radical Treatment


Aug 97 midway thru TPZ/RT Abnormality following Radical Treatment


Dec 97 – residual induration, PET – Abnormality following Radical Treatmentve; RND, path –ve


Therapeutic monitoring
Therapeutic Monitoring Abnormality following Radical Treatment

Baseline Evaluation

4 weeks into treatment

  • Left base tongue primary with bulky bilateral upper deep cervical lymphadenopathy

  • Clinical progression on treatment

p710


Sequential scans
Sequential Scans Abnormality following Radical Treatment

Comparison of CT and PET response

Early metabolic CR

Partial, late CT response

p710


Sequential clinical response
Sequential Clinical Response Abnormality following Radical Treatment

Long lag between metabolic and clinical response

Complete local pathological response confirmed

p710


Post treatment assessment
Post-treatment assessment Abnormality following Radical Treatment

  • 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
Patients and Methods Abnormality following Radical Treatment

  • 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 Abnormality following Radical Treatment

PET only

Conv only

Neither

Total accurate on PET

Total accurate on Conv

PET +ve predictive value

PET -ve predictive value

Number correct

16

23

2

3

39

18

95% (CI 77%-100%)

83% (CI 63%-95%)

Conventional Assessment vs PET in 44 Evaluable Patients


Impact of pet on patient management
Impact of PET on Patient Management Abnormality following Radical Treatment

  • 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
Survival by PET findings Abnormality following Radical Treatment


Utility of pet to obviate planned neck dissection
Utility of PET to Obviate Planned Neck Dissection Abnormality following Radical Treatment

  • 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
Neck node study Abnormality following Radical Treatment– 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
Patient population Abnormality following Radical Treatment

  • 39 patients median age 55 (37-89)

    • Male 29

    • Female 10

  • Primary sites

    • Oropharynx 31

    • Larynx 5

    • Hypopharynx 3


Pet scans
PET scans Abnormality following Radical Treatment

  • 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 and N staging Abnormality following Radical Treatment


Treatment
Treatment Abnormality following Radical Treatment

  • Chemo-radiotherapy 34

    • Chemoboost 22

    • TPZ/cisplat regimen 12

  • Radiotherapy alone

    • Standard fractionation 1

    • Altered fractionation 4


Results n 39
Results Abnormality following Radical Treatment(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
Results Abnormality following Radical Treatment(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
Predictive value of PET Abnormality following Radical Treatment

  • 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
Explanatory hypothesis Abnormality following Radical Treatment

  • 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
Time frame important Abnormality following Radical Treatment

  • 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
Outcomes in Peter Mac series Abnormality following Radical Treatment


Current peter mac protocol
Current Peter Mac protocol Abnormality following Radical Treatment

Primary CR Neck NR or PD

8 weeks Clinical Exam

Neck Dissection

Primary CR Neck PR

12 weeks Clinical Exam & CT/MRI

Neck CR

Observe*

PET +

Selective Neck Dissection

PET Scan

Node >1cm stable for ≥2 mths

PET -

*Regular FU schedule

#Monthly until CR achieved

Observe#


Therapeutic monitoring does metabolic response predict survival in nsclc
Therapeutic Monitoring Abnormality following Radical TreatmentDoes Metabolic Response Predict Survival in NSCLC?


Aims of Study Abnormality following Radical Treatment

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
Metabolic Response Assessment Abnormality following Radical Treatment

  • 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
Metabolic Response Abnormality following Radical Treatment

Primary metabolic CR with associated radiation pneumonitis


Complete Response Abnormality following Radical Treatment:

(Tumoral uptake=Mediastinal)

Before chemo-RT 2 months post treatment


Partial Response Abnormality following Radical Treatment

Baseline study

Persistent disease 14 weeks post RT

CR post salvage surgery: Path confirmed viable tumor


PET Responses in 88 Patients Abnormality following Radical Treatment

Scans performed median 70 days post RT

CR 40 (45%)

PR 32 (36%)

NR 5 (6%)

PD 11 (13%)


Survival by PET Response Abnormality following Radical Treatment


Survival by pet response grouped for lung radiotoxicity
Survival by PET Response Abnormality following Radical TreatmentGrouped for Lung Radiotoxicity

Hicks et al, IJROBP, in press, 2003

no


Conclusions – PET Response Abnormality following Radical Treatment

  • 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
Overall Conclusions Abnormality following Radical Treatment

  • 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
Acknowledgements Abnormality following Radical Treatment

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


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