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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

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


Lester j peters md

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


Lab based predictive assays

Lab-based Predictive Assays


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


Lester j peters md

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


Lester j peters md

Small Animal PETValidation Studies in Mice – F-18 Fluoride

18F fluoride PET bone scan of a mouse


Lester j peters md

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


Human studies with novel tracers at peter mac

Human Studies with Novel Tracers at Peter Mac


Lester j peters md

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


Lester j peters md

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


Lester j peters md

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


Lester j peters md

Imaging for Hypoxia with FAZA

FDG

FAZA

  • T3 N1 SCC base of tongue

  • Central uptake in viable tumor and in left cervical node


Lester j peters md

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


Patient characteristics n 122

Patient Characteristics(n=122)


T4 scc palate and oropharynx

T4 SCC palate and oropharynx


Outcome

Outcome

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


Time to loco regional failure n 122

Time to Loco-Regional Failure(n=122)


Failure free survival

Failure-free Survival


Overall survival

Overall Survival


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 f miso

Hypoxia Imaging – F MISO


Lester j peters md

Hypoxia Imaging

FDG

(Glucose)

F MISO

(Hypoxia)

Carcinoma of larynx with hypoxic neck nodal mass

p1597s0s1


Lester j peters md

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


45 patients had baseline imaging of tumor hypoxia with f miso

45 patients had baseline imaging of tumor hypoxia with F-MISO


Failure pattern in f miso scanned patients

Failure Pattern in F-MISO Scanned Patients

Rischin et al, unpublished data, 2003


Time to locoregional failure by treatment and hypoxic status

Time to Locoregional Failure by Treatment and Hypoxic Status


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


Lester j peters md

Jul 97 T3 N3 SCC L tonsil, post incisional Bx neck node


Lester j peters md

Close-up neck


Lester j peters md

Aug 97 midway thru TPZ/RT


Lester j peters md

Dec 97 – residual induration, PET –ve; RND, path –ve


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%)


Survival by pet findings

Survival by PET findings


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)


T and n staging

T and N staging


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


Outcomes in peter mac series

Outcomes in Peter Mac series


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#


Therapeutic monitoring does metabolic response predict survival in nsclc

Therapeutic MonitoringDoes Metabolic Response Predict Survival in NSCLC?


Lester j peters md

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


Lester j peters md

Complete Response:

(Tumoral uptake=Mediastinal)

Before chemo-RT 2 months post treatment


Lester j peters md

Partial Response

Baseline study

Persistent disease 14 weeks post RT

CR post salvage surgery: Path confirmed viable tumor


Lester j peters md

PET Responses in 88 Patients

Scans performed median 70 days post RT

CR 40 (45%)

PR32 (36%)

NR 5 (6%)

PD11 (13%)


Lester j peters md

Survival by PET Response


Survival by pet response grouped for lung radiotoxicity

Survival by PET Response Grouped for Lung Radiotoxicity

Hicks et al, IJROBP, in press, 2003

no


Lester j peters md

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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