PET

in Oncology.
Walid Omar, MD Nuclear Medicine Dept. NCI
NCI

Presentation outline:
What is Positron Emission Tomography (PET)

History of PET development. PET tracers and future developments. Clinical Applications in oncology. Evaluation of treatment response. New developments in PET scanners.

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COINCIDENCE IMAGING Positron Decay Positron Annihilation Two 511 keV photons Emitted simultaneously 180 apart

18F

e+ e+ + e- =
180

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PET
solution PET tracers annihilate with emission of two 511 Kev gamma rays emitted at 180 degree apart.

12 % energy resolution

2D

3D

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History :
1975 PHILIPS & Hoffman (PET)
24 (5cm) NaI TL detectors in hexagonal array pattern FBP

1978 (PET II)

48 (3.75 cm) NaI TL detectors in hexagonal array pattern First clinical PET

1981 (Derenzon & Budinger)

developed the circular geometry

Bismuth Germanate Crystal (BGO)/(LGO) Cooling system.

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Requirements for a PET facility?

Cyclotron. Radiochemistry lab. PET scanner or PET/CT. Data processing Staff Distribution of PET tracers.

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Discovery

LS16

Gemini

PET CT

REVEAL-RT function + anatomy

REVEA L-XL

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The changing focus of PET ...

PET applications worldwide

mid 80s
neurology cardiology
75%

2004
5% 5%

10%

15%

90%
> 300.000 procedures p.a.

< 10.000 procedures p.a.

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oncology

Tx.

neurology
Em. FDG

oncology

homogenous organ limited variety high activity conc. Uniform attenuation single organ - single FOV
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Inhomogeneous body wide variety lower activity conc. high non uniform attn. WB - multiple FOV

PET RADIOPHARMACEUTICALS
PET tracers in Oncology.

Fluodeoxyglucose F-18 Water O-15 Sodium acetate C-11 Carbon monoxide C-11 Fluoride F-18 Methionine C-11 Thymidine C-11 Ammonia N13
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FLUORINE-18 FLUORODEOXYGLUCOSE (F-18 FDG)

Extracellular Intracellular
Hexokinase

Glucose

Glucose

Glucose-6-P

Hexokinase

FDG

FDG

FDG-6-P
G-6-Phosphatase

Metabolic pathway of glucose and 18F FDG

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Oncological PET
HCFA / CMS Approved
Lung Malignant Lymphoma Colorectal Malignant Melanoma Esophagus Head & Neck Cancer Breast Brain
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Melanoma Pancreas Bone & Soft Tissue Ovarian Cancer. Thyroid Ca.

Normal PET Scan

AC / WB image. No bladder Artifacts. Heart and kidneys are normally seen.

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NSCLC

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SUMMARY OF EVIDENCE FOR FDG PET IN LUNG CANCER

For Staging: An estimated 37% change was noted
in management effect, based on 1,565 patient studies

Gambhir S.S., et al. A Tabulated Summary of the FDG PET Literature J Nucl Med; Vol. 42(5):1S-93S, 2001
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COLON CANCER

Metastatic Colon Cancer

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Ga-67 H D.

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Hodgkin Disease

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H D.

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Advantages of Nuclear Medicine?

Metabolic imaging

Quantitation is possible especially with PET PET provides ideal solution to quantitate
tumor biological parameters such as metabolism, receptor quantity, cell proliferation and uptake of therapeutic agents.

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EVALUATING TREATMENT RESPONSE Tumor response to chemotherapy:

Biologic and metabolic decrease in metabolic function and trapping of radiopharmaceuticals occurs: Very early after initiation of treatment Precedes clinical decrease in tumor size Precedes decrease in size detected by X-ray, CT or MRI. Important to be evaluated early in the course

of treatment in order to either continue on same chemotherapy or change to a different regimen before bone marrow depression.
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NHL Pre-chemotheray

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NHL Post-chemotheray

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FDG-PET PREDICTION OF RESPONSE TO NEOADJUVANT CHEMOTHERAPY IN CARCINOMA OF THE GE JUNCTION

N=22

N=15

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Weber, et al., J Clin Oncol 19:3058, 2001

FDG-PET PREDICTION OF RESPONSE TO NEOADJUVANT CHEMOTHERAPY IN CARCINOMA OF THE GE JUNCTION

Baseline Day 14 Responder

Nonresponder

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Weber, et al., J Clin Oncol 19:3058, 2001

METABOLIC RESPONSE TO GLEEVEC IN GIST

DANA-FARBER CANCER INSTITUTE

Baseline months

24 hours

7 days

2 months

5.5

AVDA-2001 Dana-Farber Cancer Institute

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OTHER PET APPROACHES FOR ASSESSING RESPONSE TO THERAPY

Monitoring
Blood flow Amino acid metabolism DNA synthesis (proliferation) Apoptosis Chemotherapeutic agents MDR substrates Hypoxia tracers Receptor ligands

Predicting

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PET RADIOPHARMACEUTICALS
Labeled chemo-theraputicagents F-18 flurodioxy uridine Hypoxia imaging agents F-18 Fluro-misonidazole. Tumor receptor status imaging agents. F-18-17B-estradiol.

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C-11 THYMIDINE
DNA precursor, incorporated into DNA Direct assessment of tumor proliferation

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C-11 THYMIDINE
Uptake in vitro correlates with tumor proliferative rate (Higashi et al., 1993) Uptake in animal tumor model correlated with viable tumor cells better than FDG uptake cells after fractionated radiotherapy (Reinhardt et al., 1997) Uptake correlated with grade in NHL (Martiat et al., 1988) More rapid decline in C-11 thymidine uptake than in FDG uptake in NSCLC responding to chemotherapy (Shields et al., 1998)
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NON-SMALL CELL CANCER: RESPONSE TO THERAPY FDG

3/14/96

Thymidine

4/09/96

coronal slices

5/22/96
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UWMC PET Center
UW MC

3-Deoxy-3-[18F]fluorothymidine (FLT)
)

Shields et al., Nature Med 1998; 11:1334 NCI

FLT-PET

Buck et al., Cancer Res 2002; 62:3331 NCI

FLT-PET IN BREAST CANCER

Pre-Treatment

Post-Treatment

Courtesy of A. Shields, NCI D M

TUMOR HYPOXIA
Hypoxic components in most solid animal tumors and presumably most human tumors Increases local tumor aggressiveness and metastatic potential Results in resistance to radiotherapy and chemotherapy Radioresistance potentially overcome by use of high-LET radiation, hyperbaric oxygenation, hyperthermia, or hypoxic-cell radiosensitizers

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MEASUREMENT OF TUMOR HYPOXIA

Oxygen electrodes
Direct measurement of extracellular O2 levels Pre-therapy O2 levels correlated with outcome of radiotherapy in cervical and head & neck cancers Invasive, technically demanding technique Requires accessible tumors Subject to sampling errors

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MEASUREMENT OF TUMOR HYPOXIA

Imaging by PET
Traditionally analogs of the radiosensitizer misonidazole Noninvasive Entire tumor sampled Repeated measurements possible Resolution limited by PET scanner

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PREDICTING RESPONSE OF ADVANCED BREAST CANCER TO HORMONAL THERAPY

Hormonal therapy
Low morbidity alternative to chemotherapy Only 50-60% of patients with ER+ breast cancer respond to hormonal therapy Suggests that receptors not always functional

Hypothesis: FDG-PET can be used to define functional estrogen receptors by detecting metabolic response to receptor agonist

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PREDICTING RESPONSE TO HORMONAL THERAPY Metabolic Flare

100 80

% Change FDG-SUV

60 40 20 0 -20 -40 -60

FDG-PET before and after 7-10 days tamoxifen in 40 pts. with advanced ER+ cancers With change 10%: PPV 91% NPV 94% for predicting response

Responders N = 21
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Non-responders N = 19

Mortimer, et al. JCO 2001; 19:2797

BREAST CARCINOMA: THERAPY FDGPET PREDICTING OF RESPONSE TO HORMONAL Before Hormonal Therapy After Hormonal Therapy
Responder

SUV=4.7

SUV=7.5

Nonresponder
SUV=5.7 SUV=5.5

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Limitations of PET
General Limitations: High cost. Require large space. High training for the operating staff is a must. Specific Limitations: FDG-is a non-specific agent. False positive uptake in granulomas. Difficult to interpret in areas of normal uptake. Depend on glucose transport, thats why not sensitive in mucine & mucinous secreting tumors.

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CT/PET Image Fusion

Guide surgery or biopsy Oncology
fibrosis vs. active tumor evaluation of therapy response uptake of FDG vs. size on CT

Radiotherapy Applications
Tailor field size to viable tumor Assessment of residual mass on CT post therapy

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Image Fusion: CT & FDG Coincidence Imaging

Epitheliod Sarcoma after resection NCI

Image Fusion: CT & FDG Coincidence Imaging

Lung Cancer: Poorly differentiated sq. C Ca Rt UC. CT & FDG concordant findings for pleural based mass. Patient to be treated by chemotherapy. NCI

Glioblastoma: Tumor recurrence

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LYMPHOMA

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CT/PET Dependable Image Quality

7 minute exam 12 minute exam 17 minute exam

120 lbs 1 min/bed

160 lbs - 2 min/bed

Images courtesy of UCLA, Dr. Czernin

250 lbs - 3 min/bed

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CT/PET

3 min/bed, five beds, 1 min CT: 16 min total

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Images courtesy of UCLA, Dr. Czernin

Ready to use synergies

The use of PET information in the RT planning process significantly improves outcome and patient management.
R. Thompson, M.D. Cedars Sinai Medical Center, Los Angeles, USA

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Selection of radiation therapy targets by means of 18F-FDG imaging (delineated by red lines) resulted in much more accurate targeting than did CT alone (delineated by yellow lines). The latter would have left untreated cancerous areas in the mediastinum
NCI Wagner H.N., Highlights 2001 Lecture: Against All Odds, Nuclear Medicine Has Thrived J Nucl Med; Vol 42(8);12N-30N.

Gated FDG study showed that a much smaller area need be irradiated than the larger area delineated by the green line, thu sparing unnecessary irradiation of the spinal cord
Wagner H.N., Highlights 2001 Lecture: Against All Odds, Nuclear Medicine Has Thrived J Nucl Med; Vol 42(8);12N-30N.

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Clinical Integration

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Therapy Connectivity
Therapy Connectivity
PET and CT DICOM Established connectivity with:
Varian, Nomos, Nucletronetc

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Therapy Positioning
Therapy Positioning with Open-Port design
Patient positioning accessories
BreastBoard HipFix Headholder

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CHALLENGES:
Higher cost

Re-designing of installation sites Patient through put Budgeting

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Thank you

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