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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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slide1
Lester J Peters MDUse 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

slide4

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
slide9

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

slide11

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

slide15

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

slide16

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

slide17

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

slide19

Imaging for Hypoxia with FAZA

FDG

FAZA

  • T3 N1 SCC base of tongue
  • Central uptake in viable tumor and in left cervical node
slide20

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

Arm 1 – Radiotherapy 70 Gy/ 7 wks

  • with “Chemo-boost” cisplat +5FU
  • Arm 2 – Radiotherapy 70 Gy/ 7 wks
  • with cisplat +tirapazamine
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
slide34

Hypoxia Imaging

FDG

(Glucose)

F MISO

(Hypoxia)

Carcinoma of larynx with hypoxic neck nodal mass

p1597s0s1

slide35

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

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
therapeutic monitoring
Therapeutic Monitoring

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

Comparison of CT and PET response

Early metabolic CR

Partial, late CT response

p710

sequential clinical response
Sequential Clinical Response

Long lag between metabolic and clinical response

Complete local pathological response confirmed

p710

post treatment assessment
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
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 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
  • 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%)
utility of pet to obviate planned neck dissection
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
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
Patient population
  • 39 patients median age 55 (37-89)
    • Male 29
    • Female 10
  • Primary sites
    • Oropharynx 31
    • Larynx 5
    • Hypopharynx 3
pet scans
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)
treatment
Treatment
  • Chemo-radiotherapy 34
    • Chemoboost 22
    • TPZ/cisplat regimen 12
  • Radiotherapy alone
    • Standard fractionation 1
    • Altered fractionation 4
results n 39
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
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
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
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
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
current peter mac protocol
Current Peter Mac protocol

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#

slide66

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
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
Metabolic Response

Primary metabolic CR with associated radiation pneumonitis

slide69

Complete Response:

(Tumoral uptake=Mediastinal)

Before chemo-RT 2 months post treatment

slide70

Partial Response

Baseline study

Persistent disease 14 weeks post RT

CR post salvage surgery: Path confirmed viable tumor

slide71

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 grouped for lung radiotoxicity
Survival by PET Response Grouped for Lung Radiotoxicity

Hicks et al, IJROBP, in press, 2003

no

slide74

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
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
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

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