Dr. Hussein Farghaly, MDDr. Hussein Farghaly, MD

Assistant professor and Assistant professor and Consultant nuclear Consultant nuclear

MedicineMedicine

Advances in oncological PET Advances in oncological PET ImagingImaging

Outline

Introduction Limitations of PET/CT imaging Advances of PET/CT Imaging: New PET radiotracer PET/CT protocols Soft Wear Enhance the specificity Insturmentation PET/MRI PEM

IntroductionIntroduction

FDG PET/CT has emerged as a powerful imaging tool for the detection of various cancers. FDG PET/CT has emerged as a powerful imaging tool for the detection of various cancers.

The combined acquisition of PET and CT has synergistic advantages over PET or CT alone The combined acquisition of PET and CT has synergistic advantages over PET or CT alone

and minimizes their individual limitations. and minimizes their individual limitations.

It is a valuable tool for staging and restaging of some tumors and has an important role in the It is a valuable tool for staging and restaging of some tumors and has an important role in the

detection of recurrence in asymptomatic patients with rising tumor marker levels and patients detection of recurrence in asymptomatic patients with rising tumor marker levels and patients

with negative or equivocal findings on conventional imaging techniques. It also allows for with negative or equivocal findings on conventional imaging techniques. It also allows for

monitoring response to therapy and permitting timely modification of therapeutic regimens. In monitoring response to therapy and permitting timely modification of therapeutic regimens. In

about one third of the patients, the course of management is changed about one third of the patients, the course of management is changed

Clinical Impact of PET/CT

Advantages of PET/CT over Conventional anatomical imaging:

• Characterizing lesions difficult to biopsy

• Detecting occult cancer

• Determining extent of cancer and response to therapy

Significant clinical impact

More accurate diagnosis

Avoidance of unnecessary tests, and (potentially) harmful procedures

Better treatment or management (PET - CT changes management in about one third of cancer patient)

Is FDG PET/CT a completely perfect test?

Limitations in FDG – Limitations in FDG – PET/CT imagingPET/CT imaging

Due to FDG:Due to FDG:

False positive False positive

False negativeFalse negative

Radiation exposure from radiotracer (8 Radiation exposure from radiotracer (8 mSv)mSv)

Due to instrumentation:Due to instrumentation:

mis-registration (motion artifact)mis-registration (motion artifact)

low spatial resolutionlow spatial resolution

Radiation exposure from CT (7 -25 mSv)Radiation exposure from CT (7 -25 mSv)

Long study timeLong study time

Limitations in FDG – Limitations in FDG – PET/CT imagingPET/CT imaging

False positive: False positive:

““Normal” uptake Normal” uptake (head & neck, muscle, brown fat, GI/GU uptake)(head & neck, muscle, brown fat, GI/GU uptake)

false-positive FDG uptake can occur in PET/CT in relation to false-positive FDG uptake can occur in PET/CT in relation to granulomatous disease or inflammation. Some benign tumors, such granulomatous disease or inflammation. Some benign tumors, such as colonic adenomas and fibroids, may also demonstrate intense as colonic adenomas and fibroids, may also demonstrate intense FDG uptakeFDG uptake

False negative:False negative: Small lesions (partial volume loss)Small lesions (partial volume loss) Hypometabolic lesions (low grade tumor, well differentiated Hypometabolic lesions (low grade tumor, well differentiated

NET, mucinous secreting tumor, RCC, some low grade NET, mucinous secreting tumor, RCC, some low grade lymphoma like small lymphocytic lymphoma, peripheral T-cell lymphoma like small lymphocytic lymphoma, peripheral T-cell lymphomalymphoma

Elevated serum glucoseElevated serum glucose

RADIOCHEMISTRY

INSTRUMENTATION HW/SW

ADVANCES IN PET IMAGING

NEW SCINTILLATION CRYSTALS

Dose reduction soft wear

PET/MRI

PEM

NEW TRACERS PET

Advances in PET Advances in PET RadiotracerRadiotracer

Glucose metabolism [Glucose metabolism [1818F]FDGF]FDG Protein synthesis C-11-methionine

Membrane function [Membrane function [1111C]CholineC]Choline

Proliferation Proliferation [[1818F]FLTF]FLT

HypoxiaHypoxia [[1818F]FMISO F]FMISO

[18F]FAZA [18F]FAZA

[64Cu]ATSM[64Cu]ATSM

ApoptosisApoptosis [[1818F]Annexin VF]Annexin V AngiogenesisAngiogenesis [[1818F]NGR-peptideF]NGR-peptide

Neuroendocrine tumorsNeuroendocrine tumors [[110110In]OctreotateIn]Octreotate

[68Ga] [68Ga]

DOTATOCDOTATOC

TRACERS for TUMOR CHARACTERIZATIONTRACERS for TUMOR CHARACTERIZATIONAdvances in PET RadiotracerAdvances in PET Radiotracer

Normal distribution of FDG and C-11 Methionine

C-11-methionineC-11-methionine

Benjamin et al; 2010 Anticancer Ther. 10(5), 609–613 (2010)

Posterior fossa glioma.

C-11-methionineC-11-methionine

(A) 18F-FDG; (B) contrast-enhanced MRI; (C) 11C-MET PET. Glioblastoma in the right frontal lobe, which is hard to delineate in the 18F-FDG PET. However, amino-acid PET with 11C-MET clearly shows the lesion with excellent tumor to background contrast.

Benjamin et al; 2010 Anticancer Ther. 10(5), 609–613 (2010)

A B C

left frontal grade II fibrillary astrocytoma left frontal grade II fibrillary astrocytoma (post-surgery and post-radiotherapy)(post-surgery and post-radiotherapy)

C-11-methionineC-11-methionine

Benjamin et al; 2010 Anticancer Ther. 10(5), 609–613 (2010)

11C-choline11C-choline

Richter et al;, Mol Imaging Biol (2009)

11C-choline11C-choline

Fifty-five-year-old patient with increasing PSA level (1.43 μg/l), 27 months after radical prostatectomy (Gleason score8). Coronal (left), axial (middle), and sagittal (right) fused image projections of PET/CT scans. Focal 11C-choline uptake (a) in right (bold arrow) and left (thin arrow) iliac region revealed lymph node involvement, not observed with 18F-FDG PET (b).

Richter et al;, Mol Imaging Biol (2009)

Pure Bronchioloalveolar Pure Bronchioloalveolar CarcinomaCarcinomaCT

[11C]Choline PET

[18F]FDG PET

SUV = 1.73

Picchio et al; current radiopharmaceutical, 2011

Dehdashti et al., Eur J Nucl Med Mol Imaging (2010 5 32:344–350

11C-Acetate11C-Acetate

Chitneni et al,; J Nucl Med 2011; 52:165–16818F-misonidazole (FMISO) PET scans in RT Planning

HYPOXIA IMAGING

[[1818F]FMISO F]FMISO

18F-misonidazole

[18F]FAZA [18F]FAZA 18F-

fluoroazomycinarabinofurano

side

[64Cu]ATSM[64Cu]ATSM64Cu-diacetylbis ( N4-

methylthiosemicarbazone)

Adapted from MacManus et al, Radiotherapy and Oncology 2013

PET/CT in Radiation Therapy planning

GEMINI TF GEMINI TF PET/CT scanner PET/CT scanner with TruFlight technologywith TruFlight technology

Outline

PET/CT principle Indeterminate lung nodules Lung cancer Staging and Restaging of known

tumor Monitoring therapy Early detection of tumour recurrence Impact on radiation therapy planning

Indeterminate lung nodules

Accounts for ≈ 20% of newly diagnosed lung cancer

CXR and CT: not accurate to differentiate benign from malignant non-calcified pulmonary nodules that are between 1-3 cm in diameter

Initial presentation in 20% - 30% of lung cancer Morphologic stability over 2 years: reliable sign

of benignity: Doubling time of malignant nodules: 30-400

days Doubling in volume results in 26% increase in

diameter

Visual Analysis:Visual Analysis: nodule activity vs mediastinal blood pool activitynodule activity vs mediastinal blood pool activity

Quantitative analysis: SUV (standardized uptake value)Quantitative analysis: SUV (standardized uptake value)

[[1818F]FDG PETF]FDG PET

Measure of metabolic activity of SPNMeasure of metabolic activity of SPN

SUV = 7.3

CT [18F]FDG PET

A SPN with SUV more than 2.5 is considered to be malignant

PIOPILN Study Prospective investigation of PET in

lung nodules 90 patients from 5 centers with indeterminate nodules (CT)

Size range: 0.7 to 4 cm

All nodules had histology: 67% were malignant

PIOPLIN and other studies: SUV > 2.5 = visual (FDG uptake >

mediastinal blood pool)

Sensitivity: 90-100% Specificity: 69-95%

False positive: Active granuloma

False negative: Bronchioalveolar, mucinous carcinoma, carcinoid

Hyperglycemia (decreases uptake by up to 50%)

Lowe VJ et al. J Clin Oncol 1998;16:1075-1084. Nomori H et al. Lung cancer 2004;45:19-27. Herder GJ et al. Eur J Nucl Med Mol Imag 2004;31:1231-1236. Lowe VJ et al. J Nucl Med 1994;35:1771-1776. Nomori H et al. Ann Thorac Surg 2005;79:984-988.

Diagnostic Accuracy of FDG PET and CT for the

Characterization of Lung Nodule

344 patients for which definite diagnosis was obtained

Prevalence of malignancy: 53% Average size: 16 mm

PETPET CTCT

Sensitivity 91.7% 95.6%

Specificity 82.3% 40.6%

Fletcher JW et al. J Nucl Med 2008;49 (2):179-185

Middle-aged woman with a 1.5 cm lung nodule

SUV is 6.2

Question

What should be done next? A. Follow-up B. Biopsy C. Chemotherapy D. Antibiotics

Question

What should be done next? A. Follow-up B. Biopsy C. Chemotherapy D. Antibiotics

Middle-aged patient with a 1.4 cm lung nodule

SUV is 1.2

Question

What should be done next? A. Biopsy B. Reassure the patient that the

nodule is benign C. Follow-up with CT at 3-6 months

interval for 2 years D. Follow-up with chest X-ray in 6

months

Question

What should be done next? A. Biopsy B. Reassure the patient that the

nodule is benign C. Follow-up with CT at 3-6

months interval for 2 years D. Follow-up with chest X-ray in 6

months

ACCP Evidenced-Based Clinical Practice

Guidelines: Recommendation for FDG PET

PET recommended: Probability of cancer low to moderate (5%-60%) and an indeterminate nodule measures at least 8-10 mm.

PET NOT recommended: SPN that has a high probability of malignancy (>60%) or nodule < 8-10 mm

Staging NSCLCT staging: tumor size T1 < 3 cm T2 > 3 cm T3 > 3 cm with chest wall, pleural, or pericardial

extension T4 with invasion of adjacent organs N staging: nodal metastases N0: no nodes N1: ipsilateral hilar nodes N2: ipsilateral mediastinal or subcarinal nodes N3: contralateral nodes or scalene/supraclavicular

nodes M Staging: distant metastases M0: no distant metastases M1: distant metastases present

FDG PET for StagingT staging:The extent of the primary tumor determines therapeutic

management.

Imaging is done to assess the size of the tumor and the extent of pleural, chest wall or mediastinal invasion.

CT and MRI are useful for confirming gross chest wall and

mediastinal invasion. But they are inaccurate in differentiation between anatomic contiguity and subtle invasion.

FDG PET alone: limited for T staging due to poor anatomic resolution, lack of anatomical landmark.

PET/CT: improve staging by clearly demarcating the actual extent of the tumor and involvement of chest wall, diaphragm, mediastinal pleura or pericardium or main bronchus (T3 staging).

Padma; et al, 2011.

T staging cont.:

similarly, it is useful to determine the involvement of mediastinal, vertebral and vital structures, such as the great vessels, trachea, esophagus or heart (T4 staging).

Also it is used to evaluate additional pulmonary nodules in the same lobe/ipsilateral lung having primary lung cancer, and determine the likelihood of malignancy in these nodules.

CT is rarely able to differentiate between reactive and malignant pleural effusion whereas malignant pleural effusion showed FDG uptake in PET (stage M1a).

It also has a role in guiding biopsy in patient with disease recurrence.

66 year-old with right hilar mass

Primary lung cawith atelectasis

Lung cancer staging scan with incidental second

primary

Coleman et al; 2006

N staging: •The precise

characterization of mediastinal lymph nodes is crucial for determining nodal (N) stage and thus resectability in patients with NSCLC.

•CT and MRI: limited by size criteria.

• FDG PET: best to detect tumor in normal size lymph nodes

CTCT Depending on size criteria on CT a lymph node with a

short-axis diameter greater than 1 cm is considered enlarged and a predictor for metastasis. However, this method has proven inaccurate. In one study, 44% of metastatic lymph nodes in patients with NSCLC measured less than 1 cm, and 77% of patients without metastatic lymph nodes had a lymph node measuring greater than 1 cm in the short-axis diameter.

Several meta-analyses have reported low sensitivities and specificities of CT in the assessment of mediastinal lymph-node involvement, ranging from 50% to 65% and from 65% to 85%, respectively.

Prenzel et al; 2003.

FDG PET/CTFDG PET/CT Depending on the metabolic activity within the

lymph node FDG PET can characterize mediastinal LN.

PET positive mediastinal findings should be histologically or cytologically confirmed due the fact that FDG is also taken by inflammatory process.

In patients with negative mediastinal PET images invasive staging can be omitted and it is estimated that the introduction of PET has reduced the number of mediastinoscopies by 65%

Also in case of central tumors, PET hilar N1 disease, low FDG uptake of the primary tumour, invasive staging with mediastinoscopy remains indicated.

Performance of different locoregional staging techniques

(adapted from Toloza 2003).

Staging PET/CT in 74-year-old woman with 2.6-cm left Staging PET/CT in 74-year-old woman with 2.6-cm left lower lobe SCClower lobe SCC

Diagnostic axial contrast-enhanced CT scanshows multiple small subcentimeter lymph nodes scattered throughout mediastinum, primarily in lower left paratracheal region.

Fused axial PET/CT image shows uptake inlower left paratracheal lymph nodes and 3-mm lower right paratracheal lymph node

With metastatic involvement, confirmed at mediastinoscopy. Given presence of contralateral lymph node metastases, patient received chemotherapy and radiation instead of surgicalresection.

Initial staging PET/CT for 56-year-old man with 1.8-cm adenocarcinoma in right upper lobe and long history of sarcoidosis

Axial contrast-enhanced CT scan shows 1.8-cm right upper lobe nodule with extensive mediastinal and hilar lymphadenopathy

Fused axial PET/CT image confirms intense uptake in right upper lobe nodule and lymph nodes. Lymph node biopsies performed during mediastinoscopy showed only granulomatous inflammation from sarcoidosis and no evidence of tumor

Given this finding, patient was sent for curative resection

M Staging: Common metastases to adrenals, skeleton, liver, brain.

FDG PET is superior to conventional imaging:

Detect metastases > ~7 mm when CT and MRI are normal or equivocal

Detect unsuspected distant metastases: ~13% of patients

Stage I: 7.5% Stage II: 18% Stage III: 24%

Change management: 18% of cases

Peterman RM et al N Engl J Med 2000;343:254-261Baum RP et al. Q J Nucl Med 2004;48:119-142.

PET/CT for the Characterization of Adrenal Masses in Patients with lung Cancer

Giles et al; AJR:192, April 2009

Bury T et al. Eur J Nucl Med 1998;25:1244-1247.

TubercolosisTubercolosis

SarcoidosisSarcoidosis

AspergillosisAspergillosis

HistoplasmosisHistoplasmosis

CryptococcosisCryptococcosis

False-positive results:False-positive results:

Inflammatory lesions (mainly granulomas)

Limitations of FDG-PET for Lung Limitations of FDG-PET for Lung Nodule Characterization and NSCLC:Nodule Characterization and NSCLC:

maxSUV: 2.6

48 year-old female with a pulmonary mass

48 year-old female with a pulmonary mass

Histological TypeHistological Type

CarcinoidCarcinoid Pure Bronchioloalveolar Car (BAC),Pure Bronchioloalveolar Car (BAC), mucinous camucinous ca neuroendocrine tumorneuroendocrine tumor Well differentiated typeWell differentiated type

Lesion Dimension: Lesion Dimension: Small lesion < 6-8 mmSmall lesion < 6-8 mm

% of viable neoplastic cells in SPN% of viable neoplastic cells in SPN

Limitations of FDG-PET for Lung Nodule Limitations of FDG-PET for Lung Nodule Characterization and NSCLC:Characterization and NSCLC:

False-negative resultsFalse-negative results

HyperglycemiaHyperglycemia: : > 200 mg/dl = PET not performed> 200 mg/dl = PET not performed

[18F]FDG PETCT

Fused

Lung nodule4 mm in diameter

?

[18F]FDG PETCT

CT- PETSPN: 4 mm in diameter

52 years woman with an infiltrative lung nodule

maxSUV: 1.9

Question

What is the differential diagnosis? A. Neuroendocrine tumor B. Bronchioalveolar carcinoma C. Infection D. All of the above

Question

What is in the differential diagnosis? A. Neuroendocrine tumor Bronchioalveolar carcinoma C. Infection D. All of the above

New Techniques to overcome Limitations New Techniques to overcome Limitations of FDG-PET in NSCLCof FDG-PET in NSCLC

Imprecise physiologic and anatomic registration, most common adjacent to the diaphragm and heart, can lead to misregistration artifact. (RESPIRATORY GATING)

Many processes with increased metabolic activity, such as infection and inflammation, show increased uptake on PET. (DUAL TIME POINT TECHNIQUE)

Tumor with low FDG uptake (Carcinoid, Carcinoid, BAC, mucinous ca, neuroendocrine tumor, Well differentiated type) OTHER PET RADIOTRACER.

Pure Bronchioloalveolar Pure Bronchioloalveolar CarcinomaCarcinomaCT

[11C]Choline PET

[18F]FDG PET

SUV = 1.73

Dual-Time-Point F-18 FDG PET/CT

E SUV 5.7

D SUV 7.1

PET/CT imaging was performed 60 and 120 minutes after injection

Seth Kligerman1 and Subba Digumarthy: Staging of Non–Small Cell Lung Cancer Using Integrated PET/CT. AJR 2009; 193:1203–1211.

Dominique Delbeke: Role of FDG PET and PET/CT Imaging in Indeterminate Pulmonary Nodules and Lung CancerCongreso Chileno de Medicina Nuclear, Santiago, Chile 13-14 Noviembre 2008.

Padma S, Shanmuuga P. and Shamily G.: Role of PET in carcinoma lung evaluation:. Journal of cancer rearach and therapeutics-April-June 2011-Volume 7-Issue 2.

Didier Lardinois: Pre- and intra-operative mediastinal staging in non-small-cell lung cancer. Swiss Med Wkly. 2011;141:w13168.

Kiyoshi Shibuya, Kenzo Hiroshima and Takehiko Fujisawa: Comparison of Endobronchial Ultrasound, Positron Emission Tomography, and CT for Lymph Node Staging of Lung Cancer. Chest 2006;130;710-718

Khaled Alkhawaldeh,, Hans-J Biersack,, Anna Henke,, and Samer Ezziddin: Impact of Dual-Time-Point F-18 FDG PET/CT in the Assessment of Pleural Effusion in Patients With Non–Small-Cell Lung Cancer. Clin Nucl Med 2011;36: 423–428)

ReferencesReferences

Why PET-CT?Why PET-CT?

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