Technology Assessment Program Report No. 10

Technology Assessment Program

Report No. 10

Positron Emission Tomography

Descriptive Analysis of Experience with PET in VA

A Systematic Review Update of FDG-PET as a DiagnosticTest in Cancer and Alzheimer’s Disease

Authors: Elizabeth Adams, R.R.T., M.P.H., Management & Program AnalystKaren Flynn, D.D.S., M.S., Manager, MDRC Technology Assessment Program

Contributors: Elaine Alligood, M.L.S., MDRC Information Center LibrarianJennifer Cheslog, MDRC Data Assistant

Report Date: December 1998

MTA 98-032

The Health Services Research and Development Service (HSR&D) is a programwithin the Veterans Health Administration's Office of Research and Development.HSR&D provides expertise in health services research, a field that examines theeffects of organization, financing and management on a wide range of problems inhealth care delivery, quality of care, access, cost and patient outcomes. Itsprograms span the continuum of health care research and delivery, from basicresearch to the dissemination of research results, and ultimately to the applicationof these findings to clinical, managerial and policy decisions.

Technology Assessment ProgramManagement Decision and Research Center (152M)Health Services Research and Development Service

Office of Research and DevelopmentVA Medical Center

150 South Huntington AvenueBoston, MA 02130

Tel: (617) 278-4469 FTS: (700) 839-4469 Fax: (617) [email protected]

[email protected]

Released July 1999

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ACKNOWLEDGEMENTS

The contributions of the following reviewers are gratefully acknowledged. The MDRC takes fullresponsibility for the views expressed herein. Participation as a reviewer does not imply endorsement.

Valerie A. Lawrence, M.D. Medical Consultant, MDRC TA ProgramAssociate Professor, Dept of MedicineUniversity of Texas Health Science CenterAudie L. Murphy VA Medical CenterSan Antonio, Texas

Dr. Matthias Perleth, MPH Dept. of Epidemiology, Social Medicine and HealthSystem ResearchHannover Medical SchoolHannover Germany

David Hailey, M.D. Director, Health Technology Assessment UnitAlberta Heritage Foundation for Medical ResearchEdmonton, Alberta Canada

Paula Corabian Research Associate, Health Technology AssessmentUnitAlberta Heritage Foundation for Medical ResearchEdmonton, Alberta Canada

Mitchell Burken, M.D. Medical OfficerCoverage and Analysis GroupOffice of Clinical Standards and QualityHealth Care Financing AdministrationBaltimore, Maryland

Ron Milhorn Senior Health Insurance SpecialistCoverage and Analysis GroupOffice of Clinical Standards and QualityHealth Care Financing AdministrationBaltimore, Maryland

Captain R.K. Leedham, Jr., R.Ph., Chief Project Management StaffM.S., BCNP Division of Medical Imaging and

RadiopharmaceuticalsCenter for Drug Evaluation and ResearchFood and Drug Administration

David Pfister, M.D Associate Attending PhysicianMemorial Sloan-Kettering HospitalAssociate Professor of MedicineCornell University Medical CollegeNew York, New York

M. Elizabeth Glenn, M.D. RadiologistWomen's Health Center

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Memphis, Tennessee

Lisa Hammond, M.D. Clinical Investigator, Institute for DrugDevelopmentCancer Therapy and Research CenterSan Antonio Cancer InstituteStaff OncologistAudie L. Murphy VA Medical CenterSan Antonio, Texas

James K. Stoller, M.D. Vice Chairman, Division of MedicineHead, Section of Respiratory TherapyDept. of Pulmonary and Critical Care MedicineThe Cleveland Clinic FoundationCleveland, Ohio

Dawn Provenzale, M.D. Director, GI Outcomes ResearchDuke University Medical CenterSenior Research AssociateCenter for Health Services Research in Primary CareVA Medical CenterDurham, North Carolina

Ladislav Volicer, M.D., Ph.D. Professor of Pharmacology and PsychiatryBoston University School of MedicineClinical Director/GRECCVA Medical CenterBedford, Massachusetts

The MDRC Technology Assessment Program wishes to thank Julie Lowery, Ph.D., Bonnie Bootsmiller,Ph.D., and Andrew Behler, M.P.H. of the VA Center for Practice Management and Outcomes Research inAnn Arbor for contributing VA registry data to the report.

The MDRC Technology Assessment Program also wishes to thank Maria Fonseca, Diane Hanks,Matthew Eberle, Kevin Rys, and the staff of the Information Dissemination Program for their help withthe report.

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Positron Emission Tomography

PREFACE

The Veterans Health Administration (VHA) has 10 positron emission tomography (PET) imagingfacilities and shares ownership and operations with some of its academic affiliates and one with theDepartment of Defense. Significant resource commitments are associated with the acquisition andoperation of these facilities.

In 1996, the MDRC Technology Assessment Program produced a technology assessment report inresponse to a request from the Office of the Under Secretary for Health for information on VHA’sexperience with PET. The Advisory Committee for the project provided guidance on the scope andcontent of the report. The assessment reported the results of: 1) systematic reviews of clinicalapplications of PET using 2-[F-18]-2-deoxy-D-glucose (FDG) in selected cancers (head and neck, lungcancer staging, solitary pulmonary nodules, breast, and colorectal) and Alzheimer’s disease,representing conditions of importance to the veteran population, and 2) surveys of and site visits to VHAPET Centers on PET utilization, center operations, and research activities.

The MDRC found that research into the clinical utility of PET for the selected oncology conditions was inits preliminary stages. Methodological weaknesses in the published literature seriously limited thevalidity of the available evidence on the accuracy of PET as a diagnostic test, and PET’s contribution toimproving outcomes had not been systematically assessed. The lack of epidemiological information inthese studies made extrapolation of study results to defined VHA populations, and subsequent planningfor these populations, difficult.

PET is an accurate diagnostic test for dementia of the Alzheimer’s type. Studies to determine whetherthis accuracy extends to confirmed Alzheimer’s disease are under way in Europe. Nonetheless, lack ofvalid estimates of the positive predictive value of PET, parallel developments in other tests, and limitedtreatment options for Alzheimer’s disease argue for continued use of PET primarily as a research tool.Accordingly, the evidence as of September 1996 did not support widespread incorporation of PETstudies into routine diagnostic strategies for the applications included in the assessment.

The site visits and surveys confirmed that VHA has made a substantial resource commitment to its PETfacilities and that VHA researchers regard PET as an important research tool. Site investigatorsidentified a wide range of research and clinical activities in VHA PET centers, but noted that theseactivities remained largely uncoordinated. The MDRC concluded that VHA should maximize the valueof its existing commitment, rather than establish additional PET centers. This could include:

q coordinating activities of VHA PET facilities and their academic affiliates to comply with FDAregulations, to identify research areas of interest to VHA, and to design multi-center studies of highmethodologic quality;

q implementing a VHA PET registry for systematic data collection and for tracking the utility of PET inselected conditions;

q supporting rigorous, prospectively designed clinical research that expands the body of PET literaturein a methodologically sound manner; and

q submitting currently unpublished data from studies of high methodological quality for peer review.

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Positron Emission Tomography1998 Update

EXECUTIVE SUMMARY

PurposeAfter the delivery of the original assessment report, the Under Secretary for Health directed theOffice of Patient Care Services to implement the assessment recommendations. VHA PETcenters collaborated on the design of the implementation process, which included initiating amulti-center VHA PET registry, supporting prospective research, and this updated systematicreview.

To produce this report the MDRC Technology Assessment (TA) Program surveyed VHA PETfacilities, used registry data, and conducted systematic reviews of the published PET literaturefrom September 1996 through December 1998 for selected cancers and Alzheimer’s disease.This report includes studies using positron emitting coincidence imaging with theradiopharmaceutical FDG to study cellular glucose metabolism.

BackgroundPET is a minimally invasive nuclear medicine imaging modality that uses the principle ofcoincidence detection to measure biochemical processes within tissues. PET may complementor supplant other imaging modalities, such as radiography, computed tomography (CT), ormagnetic resonance imaging (MRI), which rely on predominantly anatomic definitions ofdisease.

Conventional positron emission coincidence imaging is accomplished using cameras specificallydesigned, or “dedicated,” for imaging positron-emitting radioisotopes. Dual-headed gammacameras are being adapted for coincidence imaging positron emitters (called “camera-basedPET”) as a lower cost and more accessible alternative to dedicated PET. Both PET systems havewhole body scanning capability.

Key Findings

Cost and ReimbursementA dedicated PET system costs from $800,000 to $2.5 million, and a cyclotron costs from $1.2million to $1.7 million, in addition to the costs of installation, construction, and operation.Camera-based PET systems sell for about $850,000. Annual operating costs vary considerably.The charge for a PET scan will depend on these cost factors, as well as the clinical indication, theradiopharmaceutical used, and caseload.

Effective January 1, 1998 Medicare began offering interim provisional coverage for FDG-PETscans using either dedicated or camera-based PET for characterizing solitary pulmonary nodulesand initial staging of suspected metastatic non-small cell lung cancer. On or after July 1, 1999Medicare expanded coverage to include detecting and localizing recurrent colorectal cancer witha rising carcinoembryonic antigen, staging and characterizing Hodgkin’s and non-Hodgkin’slymphoma in place of a gallium scan or lymphangiogram, and identifying metastases inmelanoma recurrence in place of gallium studies.

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The national average payment is $1,980 per scan, excluding the professional component. HCFAwill collect and analyze claims data and data from other sources to determine the medicaleffectiveness of PET in managing these conditions, after which HCFA will decide the extent towhich it should modify the coverage policy.

RegulationRecent changes in FDA regulation now permit PET imaging facilities that manufactureradiopharmaceuticals on-site to continue in accordance with the positron emission compoundingstandards and the official monographs of the United States Pharmacopoeia. FDA has eitherapproved or cleared for marketing both PET systems to image radionuclides in the body.

Experience in VHA• VHA continues its moratorium on adding more dedicated PET facilities within the system.

Many VA medical centers are modifying dual-headed gamma cameras for coincidencedetection.

• A survey of active funded research at VHA PET sites underscores the importance of PET asa basic research tool. Most of the research is in neurology and cardiology and is funded by arange of private and public VA and non-VA sources.

• There has been an increase in the number of diagnostic PET scans, particularly in oncology.Lung cancer staging was the most common oncology indication among VHA PET sites inFY 1998.

• VHA is maximizing its investment in PET by developing a PET registry to collect criticalpatient information, funding rigorous, prospectively designed clinical research, and trackingthe published peer-reviewed PET literature available in the public domain.

• The MDRC TA Program is coordinating a joint project with other members of theInternational Network of Agencies for Health Technology Assessment (INAHTA) to producea report on the use of PET among countries represented by INAHTA members.

Evidence of effectivenessThe existing evidence argues against routine clinical use of PET for diagnosing Alzheimer’sdisease until more effective treatments and risk modification interventions for Alzheimer’sdisease are developed, and until meaningful and robust predictive values are obtained from anongoing European multicenter PET study. The systematic reviews indicate that the datasupporting the use of either dedicated or camera-based PET system with FDG in managingpatients with selected cancers are deficient.

• The evidence for using camera-based PET in oncology is limited to one small preliminarystudy in the tertiary-care setting, comparing camera-based PET to dedicated PET using nosuitable reference standard. Accordingly, it did not meet the inclusion criteria for thisreview.

• Included studies assessed dedicated PET as a complement to or replacement for anatomicimaging modalities, as a noninvasive alternative to invasive procedures, or as a method forincreasing the diagnostic certainty for performing an invasive procedure. Studies focused onthe technical feasibility of using dedicated PET and on defining diagnostic accuracy in thetertiary care setting.

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• Studies generally enrolled highly selected patients and failed to adequately describe theprevious work up or the size or composition of the referral base from which the patientsample was drawn. All had at least one of the methodologic biases often found in diagnosticimaging test evaluations, and their presence will tend to inflate estimates of diagnosticaccuracy. Methods for defining disease on PET imaging have not been standardized and maylimit the generalizability of findings across institutions.

• The few studies reporting the influence of PET on changes in diagnostic certainty and/ortreatment planning were usually retrospective case series that were not originally designed todocument these changes and were not systematically conducted or reported as such. Someauthors used likelihood ratios and predictive values to define PET’s clinical usefulness, butproper interpretation of these estimates is conditioned on what was known about the patientbefore the test and on deriving PET results independently of other test results. None of thestudies met both conditions, and the influence of PET on diagnostic certainty and subsequenttreatment planning could not be determined.

Conclusions/Recommendationsq VHA continues its commitment to delivering high quality patient care and to rational

resource management through its support of VHA PET centers, carefully appraising the PETliterature to identify areas in need of research, and funding rigorous, prospective clinicalresearch.

q The prevailing evidence does not support the use of either dedicated or modified camera-based PET as a diagnostic test for the applications in this review. The TA Program identifiedseveral methodologically rigorous studies of other diagnostic imaging modalities that couldserve as models for designing higher quality PET research.

q Systematic reviews from other technology assessment agencies, which used methods similarto VHA’s, derived similar conclusions. As in VHA, patients with cancer constitute aconsiderable burden to the health systems represented by these agencies, and there is growingsupport for assessing either PET modality in the work up of these patients. Accordingly,agencies identified the uses for PET in oncology, particularly staging non-small cell lungcancer, as major topics for research.

q Several cooperative trials, including a VHA Cooperative Study of PET in solitary pulmonarynodules, are ongoing or planned. Clinicians should await the results of these efforts beforeincorporating PET into routine diagnostic strategies.

q Individuals interested in clinical PET would benefit from an accessible central repositorycontaining information on existing and proposed rigorously designed cooperative trials ofPET. This source could help guide the diffusion of PET into clinical care, as its usefulnessand contribution to improved patient outcomes are appropriately evaluated.

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TABLE OF CONTENTS

I. INTRODUCTION ............................................................................................................. 1

II. DESCRIPTION OF TECHNOLOGY ............................................................................... 1A. Instrumentation............................................................................................................. 1B. Radiopharmaceutical.................................................................................................... 2C. Data Analysis................................................................................................................ 2D. Potential Roles for PET................................................................................................ 3

III. REGULATION AND REIMBURSEMENT..................................................................... 4

A. The Food and Drug Administration (FDA).................................................................. 4B. Health Care Financing Administration (HCFA) and Medicare.................................... 4

IV. ACCESS AND COST........................................................................................................ 6

V. EXPERIENCE IN VHA..................................................................................................... 6 VI. METHODS FOR THE SYSTEMATIC REVIEW ............................................................ 9

VII. APPRAISAL OF THE LITERATURE............................................................................ 11

A. Data Synthesis ............................................................................................................ 12

VIII. PUBLISHED FINDINGS ................................................................................................ 12A. Head and Neck Cancer............................................................................................... 13B. Breast Cancer.............................................................................................................. 19C. Non-Small Cell Lung Cancer..................................................................................... 26D. Solitary Pulmonary Nodules ...................................................................................... 35E. Colorectal Cancer ....................................................................................................... 40F. Alzheimer’s Disease ................................................................................................... 46

IX. ONGOING CLINICAL STUDIES AND ON-LINE RESOURCES ............................... 51

X. OTHER SYSTEMATIC REVIEWS OF PET................................................................. 52

XI. CONCLUSIONS.............................................................................................................. 54A. Experience in VA....................................................................................................... 54B. Systematic reviews..................................................................................................... 54

XII. REFERENCES ..............................................................................................................R-1

XIII. EPILOGUE.................................................................................................................... E-1

XIV. APPENDIX 1: Methods For The Systematic Review.................................................A1-1

XV. APPENDIX 2: Models Of High Quality Efficacy Studies of Diagnostic ImagingTechnologies ................................................................................................................A2-1

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XVI. APPENDIX 3: Active Funded Research at VHA PET Facilities as ofOctober 1, 1998...........................................................................................................A3-1

XVII. APPENDIX 4: Data Abstraction Tables of Included Diagnostic Efficacy Studies of FDG-PET in Cancer .............................................................................................................A4-1

XVIII. APPENDIX 5: Technology Assessments of PET Produced by OtherOrganizations ............................................................................................................. A5-1

LIST OF TABLES AND FIGURESTable 1: Pricing of New PET Scan Indications Approved by HCFA................................................................................5Table 2: VHA PET Facilities and Sharing Partners .............................................................................................................7Table 3: Diagnostic-specific Utilization Data Across VHA PET Facilities for FY 1998..............................................8Table 4: Systematic Review Protocol...................................................................................................................................10Table 5: Summary of the Technical Efficacy of Camera-based PET in 31 Patients with 109 Lesions.....................12Table 6: Characteristics of Diagnostic Accuracy Studies of FDG-PET of Patients with Head and

Neck Cancer...............................................................................................................................................................16Table 7: Summary of Diagnostic Accuracy Studies of FDG-PET in Head and Neck Cancer....................................18Table 8: Characteristics of Prospective Studies of Axillary Lymph Node (N) Staging with FDG-PET in

Patients with Potentially Operable Breast Cancer...............................................................................................21Table 9: Characteristics of Studies using FDG-PET to Stage Recurrent Disease and Metastases in Patients

with Breast Cancer....................................................................................................................................................22Table 10: Summary of Diagnostic Accuracy Studies of PET and Alternatives in Breast Cancer................................25Table 11: Characteristics of Prospective Studies of Mediastinal Lymph Node (N) Staging with FDG-PET

In Patients with Potentially Operable NSCLC.....................................................................................................28Table 12: Characteristics of Prospective Studies of Distant Metastases (M) Staging with FDG-PET in

Patients with NSCLC...............................................................................................................................................30Table 13: Summary of Diagnostic Accuracy Studies of PET and Alternatives in Staging Lung Cancer...................33Table 14: Characteristics of Studies Using FDG-PET of Patients with Radiographically Indeterminate

Solitary Pulmonary Nodules ...................................................................................................................................37Table 15: Summary of the Diagnostic Accuracy and Diagnostic Thinking Efficacy Studies of PET in

Indeterminate Solitary Pulmonary Nodules (SPN) .............................................................................................39Table 16: Characteristics of Studies of Pre-operative Staging with FDG-PET in Patients with Suspected

Recurrent Colorectal Cancer...................................................................................................................................43Table 17: Summary of Diagnostic Accuracy Studies of FDG-PET in Colorectal Cancer.............................................45Table 18: Summary of Recent Technical Efficacy Studies using FDG-PET in Alzheimer’s Disease........................49Table 19: Active NIH Trials of FDG-PET in Selected Cancers and Alzheimer’s Disease...........................................51Table 20: Methodologic Quality of Diagnostic Accuracy Studies of FDG PET in Selected Cancers.......................E-2

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I. INTRODUCTION

VHA is committed to improved quality of care and outcomes for veterans and to rationalresource management. As health care decision making transitions from a rationale based onresources and opinions to a rationale based on evidence from research, VHA uses technologyassessment (TA) processes and information to guide evidence-based decisions. Health ServicesResearch and Development Service, through the Management Decision and Research Center(MDRC), produces and disseminates TA information in the form of systematic reviews of theliterature. VHA uses these reviews to support clinical policy and focus on areas in need offurther research.

For example, after delivery of the original MDRC PET technology assessment (Flynn, 1996), theUnder Secretary for Health directed the Office of Patient Care Services to implement theassessment findings and recommendations. As a result, VHA continued its moratorium onadding more dedicated PET scanners to its system. A new VHA cooperative study incorporatedstudy design suggestions from the initial assessment. VHA PET Center Directors wereinstrumental in designing the implementation strategies, which included initiating a multi-centerVHA PET registry, completing a rigorous single-site outcome study, and updating the 1996MDRC PET systematic review.

In this update, the MDRC used evidence-based medicine frameworks and methodology toproduce systematic reviews of the peer-reviewed PET literature from September 1996 throughDecember 1998. It reviews the performance of dedicated PET systems and gamma camerasystems with coincidence detection capabilities in selected cancers of the head and neck, breast,and colo-rectum, lung cancer staging, solitary pulmonary nodules, as well as Alzheimer’sdisease. The report also contains:

• clinical and research experience across VHA PET facilities;• VHA implementation strategies for recommendations made in the first report;• ongoing multi-site clinical trials of PET for the indications reviewed in the report;• findings and recommendations from reviews of PET conducted by other technology

assessment agencies; and• a description of an international collaboration studying PET use among countries represented

by the collaboration.

II. DESCRIPTION OF TECHNOLOGY

A. Instrumentation

Positron Emission Tomography (PET) is a minimally invasive nuclear medicine imagingmodality that uses radiopharmaceuticals to capture and measure biochemical processeswithin tissues. PET, like other nuclear medicine techniques, defines disease in terms ofquantifiably abnormal regional chemistry. PET may complement other imagingmodalities, such as radiography, computed tomography (CT), or magnetic resonanceimaging (MRI), which rely on predominantly anatomic definitions of disease.

PET imaging employs radioactive isotopes that decay by emitting a positively chargedelectron, called a positron, from the nucleus. The positron collides with a negatively

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charged electron resulting in two high energy (511 keV) photons that travel in oppositedirections. PET uses the principle of coincidence detection to form the raw image. Thatis, radiation detectors are arranged in a ring around the patient to allow for simultaneous(coincidence) detection of the two photons. The exact site of origin is recorded, and across-sectional image is displayed.

Dedicated PET systems are optimized for high energy dual photon coincidence detection.Two modified forms of single photon emission computed tomography (SPECT) are nowavailable for imaging positron emitters and may be a less costly alternative to dedicatedPET (Jarrit and Acton, 1996):

• dual-headed SPECT cameras adapted for coincidence detection, called “camera-based” PET, or

• multi-headed SPECT cameras adapted with special collimators for high energy(511keV) photon absorption.

Both Jarrit and Acton (1996) and Coleman (1997) emphasized that neither modifiedSPECT system is optimized for clinical use, particularly in oncology. Lower sensitivityrestricts their use to studies using isotopes with longer half-lives, and performance andcost data comparing either system to dedicated PET are limited. These authors cautionagainst the premature use of these systems, which could be detrimental to the futureacceptance of both dedicated PET and modified PET systems.

In light of recent federal regulatory changes (See Section 111-Regulation andReimbursement) this report will address only dual-headed gamma cameras adaptedfor coincidence imaging (“camera-based” PET) and dedicated PET systems.

B. Radiopharmaceutical

The most widely used radiopharmaceutical in PET imaging is the cyclotron-producedFDG. FDG is a D-glucose analog used to study cellular glucose metabolism. Sincemany diagnostic PET studies rely on FDG, its availability is critical to a facility thatwishes to conduct clinical studies using either dedicated or camera-based PET systems.

C. Data analysis

PET and other nuclear medicine image patterns represent spatial and temporalarrangements of the physiological or biochemical process under investigation. There aremany ways to detect and compare these patterns such as visual analysis of metabolicpatterns, region of interest (ROI) analysis where the regions are hand-drawn or placed(sometimes with coregistration with anatomic images), and neural networks. PET datamay be managed by using absolute metabolic values or by normalizing to a referencevalue to generate metabolic ratios.

D. Potential roles for PET

Flynn (1996) summarized the general rationale for the use of PET in oncology. PET maydetect abnormalities in tissue biochemical and physiological processes caused by manyforms of cancer. Reliance on tumor histology and anatomy limits the oncologist’s tools

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for selecting optimal treatment, and adding metabolic data from PET may expand theoncologist’s ability to optimize treatment. Finally, monitoring metabolic responses totreatment could allow early redirection of therapy. Several potential applications for PETin oncology were noted:

• Detecting tumors (which may employ coregistration techniques that combine PETand anatomic imaging into a single image);

• Staging (particularly using whole-body imaging methods) although there is a lowerlimit to the size of metastases that can be detected by PET;

• Detecting local disease recurrence, since anatomically-based imaging is often limitedby the effects of treatment;

• Predicting tumor response to chemotherapy; and• Monitoring treatment.

Studies of Alzheimer’s disease and other neurologic and psychiatric conditions predatestudies of PET for other diagnostic applications and are prevalent in the PET literature.PET allows qualitative and quantitative evaluation of cerebral physiology and explorationof the biochemical bases for clinical diseases. FDG PET brain studies have been used formany research and clinical purposes related to the central nervous system. These include(Hoffman, 1993):

• defining the magnitude and distribution of normal local cerebral glucose metabolism,and the effects of age and sex on metabolism;

• locating seizure foci in patients with partial complex seizures who are potentialsurgical candidates for temporal lobectomy;

• assessing brain tumors for degree of malignancy at diagnosis, persistent postoperative tumor, differentiating high- from low-grade tumors and radiation necrosisfrom persistent tumor;

• evaluating schizophrenia, affective disorders, obsessive-compulsive disorder;• studying cerebral metabolism in cerebrovascular disease; and• defining regions of altered glucose metabolism in various forms of dementia such as

Alzheimer’s disease, Pick’s disease, and Huntington’s disease.

Expanded roles for PET in selected applications will be discussed in Section VIIIPublished Findings for each application.

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III. REGULATION AND REIMBURSEMENT

A. The Food and Drug Administration (FDA)

FDA has either approved or cleared for marketing dedicated PET scanners and coincidentimaging gamma cameras to image radionuclides in the body. To date, the FDA hasapproved two PET radiopharmaceuticals for clinical use:

• Rubidium (82Rb), limited to rest alone or rest with pharmacologic stress PET scans, isused for noninvasive imaging of the perfusion of the heart for the diagnosis andmanagement of patients with known or suspected coronary artery disease.

• FDG indicated for identifying regions of abnormal glucose hypometabolismassociated with foci of epileptic seizure. Approval for use is restricted to TheMethodist Medical Center in Peoria, Illinois.

In the Food and Drug Modernization Act, which was signed into law on November 21,1997, Congress directed the FDA to develop new approval procedures and appropriatecurrent good manufacturing practice requirements for PET drug products. FDA may notrequire the submission of new or abbreviated new drug applications for PET drugproducts, which are not adulterated, for a period of 4 years after the date of enactment ofthe Modernization Act or for 2 years after FDA develops the new procedures, whicheveris longer. FDA has begun developing these procedures.

In the meantime, PET drug products may be manufactured for clinical use providing theyare produced in accordance with the positron emission compounding standards and theofficial monographs of the United States Pharmacopoeia. These standards are to assurethat PET drug products are safe and have the identity, strength, quality, and purity thatthey are represented to possess.

B. Health Care Financing Administration (HCFA) and Medicare

A health technology review conducted by the Center for Practice and TechnologyAssessment (formerly the Office of Health Technology Assessment), Agency for HealthCare Policy and Research (1998) provided the basis for Medicare’s first coverage policyfor PET scans performed on or after March 14, 1995 (HCFA, AB972760):

• PET scans using Rubidium (82Rb), done at rest or with pharmacological stress, fornoninvasive imaging of the perfusion of the heart for the diagnosis and managementof patients with known or suspected coronary artery disease. Coverage is limited toPET scans used in place of SPECT or following an inconclusive SPECT scan, whichprovide information deemed necessary to determine treatment intervention.

In an agreement with the Chairman of the Senate Appropriations Committee in late 1997,the Secretary of Health and Human Services committed to expanding Medicare coverageof PET scans on an interim basis to include diagnosing solitary pulmonary nodules andinitial lung cancer staging (Stevens, 1997). Effective January 1, 1998, FDG-PET scanswill be covered when performed using either dedicated or camera-based PET system toimage radionuclides in the body for the following conditions (HCFA, 3b4120):

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• characterizing solitary pulmonary nodules (SPNs) for the primary purpose ofdetermining the likelihood of malignancy to plan treatment. Coverage is limited toclaims that include evidence of the initial detection of a primary lung tumor, usuallyby CT.

• initial staging of suspected metastatic non-small cell lung cancer in thoracic(mediastinal) lymph nodes in patients with pathologically confirmed primary lungtumor, but whose extent of disease has not yet been established. Coverage is limitedto claims that include evidence of confirmed primary tumor, concurrent CT, andfollow-up lymph node biopsy.

The use of routine biopsy following a negative PET scan is considered inappropriate inthese conditions, and payment for biopsy will be denied unless the claim is supported byevidence explaining the medical necessity of the biopsy.

After an expedited review of scientific information presented at a town hall meeting inJanuary 20-21, 1999, HCFA agreed to expand coverage for PET scans performed on orafter July 1, 1999 to diagnose and manage the following three indications:

• detecting and localizing recurrent colorectal cancer with rising carcinoembryonicantigen (CEA);

• staging and characterizing both Hodgkin’s and non-Hodgkin’s lymphoma in place ofa gallium scan or lymphangiogram; and

• identifying metastases in melanoma recurrence in place of gallium studies prior tosurgery.

Table 1: Pricing of New PET Scan Indications Approved by HCFA*

HCPCSCodes Description

National Average Paymentfor Technical Component**

G0125 PET lung imaging of solitary pulmonary nodules usingFDG, following CT

$1,980

G0126PET lung imaging for initial staging of solitarypulmonary nodules using FDG, following CT or ofpathologically diagnosed non-small cell lung cancer

$1,980

G0163 PET, whole body, for recurrence of colorectal orcolorectal metastatic cancer

$1,980

G0164 PET, whole body, for staging and characterizinglymphoma $1,980

G0165 PET, whole body, for recurrence of melanoma ormelanoma metastatic cancer $1,980

*From www.hcfa.gov/pubforms/14%5Fcar/3b4120.htm**technical component only, including payment for radiotracer, using revenue code 404. Claims for professional componentshould user modifier 26.

Medicare coverage is conditioned on the ability of PET to affect the management andtreatment of patients with these cancers. HCFA will collect and analyze claims data, anddata from other sources, to determine the medical effectiveness of PET in managing theseconditions. After sufficient claims data have been collected, HCFA will decide the extentto which it should modify the coverage policy.

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IV. ACCESS AND COST

The Institute for Clinical PET (1999) reports that there are nearly 147 facilities with coincidencedetection capability in the United States. There are 10 dedicated PET facilities in the VHAsystem, making VHA one of the largest owners of dedicated PET scanners by any single healthsystem in the world.

ECRI (1996) reports that the cost of a PET scanner ranges from $800,000 to $2.5 million,excluding costs associated with installation, construction, and operation, and a cyclotron costsfrom $1.2 million to $1.7 million. Annual operating costs vary considerably and may includepersonnel salaries, scanner and cyclotron supplies, service and maintenance contracts, equipmentamortization, and other indirect costs. Ultimately, what a PET facility charges for a PET scanwill depend on these factors, as well as the clinical indication, the radiopharmaceutical used, andcaseload (Flynn, 1996).

Currently, there is a moratorium on adding PET facilities in VHA. Many VHA medical centerswithout access to PET facilities are adapting gamma cameras for coincidence imaging. The costof upgrading dual-headed gamma cameras for coincidence imaging is approximately $250,000;dual-headed gamma cameras without the upgrade sells for about $600,000 (ECRI, 1996).

V. EXPERIENCE IN VHA

Table 2 lists VHA PET (dedicated) sites and their sharing partners. In all but two sites, both thecamera and cyclotron are in the same location. However, ownership of the camera and cyclotronvaries across sites (Flynn, 1996). All sites have access to FDG.

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Table 2: VHA PET Facilities and Sharing Partners

VHA PET Facility VISN Facility Location Sharing PartnerVA Connecticut Health Care SystemVAMC West Haven, Connecticut 1 VAMC Yale University

VA West New York Health Care SystemVAMC Buffalo, New York

2 VAMC(cyclotron at sharing partner)

State University of New York atBuffalo

VA Pittsburgh Health Care System VAMCPittsburgh, Pennsylvania 4 Sharing Partner UPMC Health Systems- Presbyterian

Richard L. RoudabushVAMC Indianapolis, Indiana

11 Sharing partner Indiana University

VAMC Ann Arbor, Michigan 11 Sharing Partner University of Michigan Ann Arbor

VAMC Minneapolis, Minnesota 13 VAMC None

St. Louis VA Medical CenterSt. Louis, Missouri 15 Sharing Partner St. Louis University

VA South Texas Health Care System VAMCSan Antonio, Texas 17 Sharing Partner-UTHSC University of Texas Health Science

Center

VA Palo Alto Health Care SystemVAMC Palo Alto, California 21

VAMC(no cyclotron, FDG purchased fromprivate source)

None

VA Greater Los Angeles Healthcare SystemVAMC West Los Angeles, California 22 VAMC Individual investigators

Research continues to constitute considerable activity conducted at VHA PET facilities. AllVHA PET facilities were surveyed for a list of active funded research at their site. The results ofthis survey are listed in Appendix III. Most are multi-year studies with funding from a range ofprivate and public VA and non-VA sponsors. The majority of funded PET research is for thestudy of neurologic conditions, followed by studies in cardiology.

The VA HSR&D Center for Practice Management and Outcomes Research, Office of Researchand Development, provided FY 1998 utilization data from the VHA PET registry for theconditions in this report (See Table 3). Of the subjects that had radiopharmaceutical dataavailable, nearly 70% were scanned using FDG, representing the radiopharmaceutical most oftenused across VHA PET sites.

Given the significant burden lung cancer represents in both the veteran and general populations,not surprisingly lung cancer was the major oncology diagnosis among VHA PET sites in FY1998. Alzheimer’s disease, colorectal cancer, and head and neck cancer have roughly equivalentnumbers of veteran and non-veterans scanned, whereas non-veterans comprise a higher portionof subjects with breast cancer, as expected. The distribution of veterans and non-veterans withinand across diagnoses may change as evidence of PET’s clinical utility is clarified, or ifreimbursement policies in either the public or private sector are altered.

December 1998


Table 3: Diagnostic-specific Utilization Data Across VHA PET Facilities forFY 1998

Diagnosis # Veterans # Non-veterans Total (% of all neurology subjects)Alzheimer’s disease 11 6 17 (3.4%)

Diagnosis # Veterans # Non-veterans Total (% of all oncology subjects)Lung cancer 246 192 438 (29.4%)*

Colorectal cancer 63 80 143 (9.5%)**

Breast cancer 1 34 35 (2.3%)

Head & neck cancer 58 52 110 (7.4%)

*excludes 8 patients with unknown veteran status**excludes 2 patients with unknown veteran status

In the 1996 assessment, the TA Program recommended that VHA maximize the value derivedfrom its existing commitment, rather than invest in additional PET centers, and suggested waysin which PET activities could be coordinated across the VHA system (See Preface). Since then,several suggestions have been implemented:

Develop and maintain a VHA PET registry

The VHA Office of Patient Care Services is providing recurring funding to the HSR&DCenter for Practice Management and Outcomes Research in Ann Arbor, Michigan todevelop and maintain a VHA PET registry. The Center is collecting annual facilityutilization data and subject-specific data from all VHA PET facilities.

Support rigorous, prospectively designed clinical research

• The VHA Office of Patient Care Services is providing funding to the VHACooperative Studies Center and to the PET Center in West Haven, Connecticut tocomplete an outcome analysis. The study addresses clinical utility, cost, utilization ofother diagnostic studies, and the impact of PET on treatment planning.

• VHA Cooperative Studies Program is funding a multi-year cooperative trial toevaluate the clinical utility of PET in characterizing solitary pulmonary nodules (SeeAppendix III, St. Louis). The Palo Alto Cooperative Studies Coordinating Center ismonitoring the study. Six VHA PET sites and four non-VHA PET sites with VAaffiliation are participating. Patient accrual started in August, 1998.

Results from these studies should clarify the evidence on the utility of FDG-PET in themanagement of patients with selected clinical conditions.

Conduct regular updates of the PET literature

The VHA Office of Patient Care Services also agreed to fund regular systematic reviewupdates of the 1996 MDRC PET Technology Assessment.

December 1998


VI. METHODS FOR THE SYSTEMATIC REVIEW

Information about the value of PET scanning in selected cancers and Alzheimer’s disease wasobtained by conducting a systematic review of the published literature. A systematic review usesa scientific approach to limit bias and to improve the accuracy of conclusions based on theavailable data. A systematic review addresses a focused clinical question, uses appropriate andexplicit criteria to select studies for inclusion, conducts a comprehensive search, and appraisesthe validity of the individual studies in a reproducible manner. With respect to the diagnostictest literature, the point of a systematic review can be to examine the ultimate value or benefitderived from the test (Guyatt, 1995).

The MDRC uses a review protocol to guide the inclusion, analysis, and summary of evidence forthis review (See Table 4 and Appendix 1). The protocol uses three analytic frameworks toappraise the literature, ensuring that studies are evaluated in a consistent, reproducible manner,and that studies included in the report conform to established scientific standards. Theseframeworks are critical to understanding the report analysis, conclusions, and recommendations.

Assign to Fryback and Thornbury hierarchical model of diagnostic efficacy

Fryback and Thornbury (1991) note that the localized view of the goal of diagnosticradiology would be that it provides the best images and the most accurate diagnosespossible. A more global view recognizes diagnostic radiology as part of a larger systemof medical care whose goal is to treat patients effectively and efficiently. Viewed in thislarger context, even high-quality images may not contribute to improved care in someinstances, and images of lesser quality may be of great value in others.

Fryback and Thornbury (1991; 1992) present an evolving hierarchical model forassessing the efficacy of diagnostic imaging procedures. Their model, with a list of thetypes of measures that appear in the literature at each level in the hierarchy, is presentedin Appendix I. Using this model, it is possible to follow the development of a diagnostictechnology and to align current research efforts with a particular level of development.

Assess the quality of individual studies of diagnostic tests using evidence-basedmedicine criteria

This assessment has adopted evidence-based medicine criteria as a requirement forassignment of studies to the “diagnostic accuracy” level of the hierarchy. These criteriawill be applied to individual studies in the report. If the criteria are not met, the studywill generally be considered insufficiently rigorous to provide the basis for patient caredecisions. However, such studies often provide useful information on the technicalcharacteristics of a diagnostic test or may provide information necessary to subsequentdiagnostic accuracy studies.

Evaluate the strength of the evidence supporting a causal link between the use of thetechnology and improved outcomes of care

Recommendations about the use of a technology should be linked to the quality of theavailable evidence, which ultimately depends on the strength of the evidence. Thestrength of the evidence relates to the overall research design and to the quality of the

December 1998


implementation and analysis, i.e. how well bias and confounding factors are controlled inthe design and conduct of a study. Attributes that strengthen the validity of findingsinclude: randomized (vs. nonrandomized), controlled (vs. uncontrolled), blinded (vs.unblinded), prospective (vs. retrospective), large (vs. small), multi-site (vs. single site),and contemporaneous (vs. historical) controls.

Table 4: Systematic Review Protocol

1) Conduct search of MEDLINE and other databases. Also search end references from retrieved articles and listings of English language, public domaintechnology assessments.

2) Apply inclusion criteria to search:• English language articles reporting primary data and published in a peer review journal (not abstracts)• studies > 12 human subjects (not animal studies) with the disease of interest• studies using dedicated PET systems or gamma camera systems adapted with 511 keV coincidence imaging capability• studies using the radiopharmaceutical 2-[18F]fluoro-2-D-glucose (FDG)• study not duplicated or superseded by subsequent study with the same purpose from the same institution• study design and methods clearly described (i.e. sufficient information to judge comparability of case and control groups, details of imaging

protocol, whether visual or quantitative analysis of PET data used, or type of PET quantitative data analysis used)

3) Retrieve full text articles meeting inclusion criteria.

4) Review full text articles and assign to level of Fryback and Thornbury (1991) diagnostic efficacy hierarchy.

5) To assess methodologic quality, apply evidence based medicine criteria to studies of diagnostic tests:• clearly identified comparison groups, ≥ 1 of which is free of the target disorder.• either an objective diagnostic standard (e.g. a machine-produced laboratory result) or a contemporary clinical diagnostic standard (e.g. a

venogram for deep venous thrombosis) with demonstrably reproducible criteria for any subjectively interpreted component (e.g., report of better-than-chance agreement among interpreters).

• interpretation of the test without knowledge of the diagnostic standard result (no test review bias).• interpretation of the diagnostic standard without knowledge of the test result (no diagnostic review bias).

6) To further refine judgment of methodological quality, grade diagnostic accuracy or thinking efficacy studies:Grade A - Studies with broad generalizability to a variety of patients and no significant flaws in research methodsGrade B - Studies with a narrower spectrum of generalizability, and with only a few flaws that are well described (and impact on conclusions can be

assessed)Grade C - Studies with several methods flaws, small sample sizes, incomplete reporting or retrospective studies of diagnostic accuracyGrade D- Studies with multiple flaws in methods, no credible reference standard for diagnosis, evidence of work up, test review, or diagnostic review

bias, or opinions without substantiating data

7) Evaluate quality of studies at each efficacy level; conduct meta analyses if appropriate.8) Rank the evidence for the degree to which it supports a causal link between technology use and improved outcomes.

Modifications made to the grading system accounted for the degree to which bias could bereasonably minimized in the study design, given the nature of the clinical work up. More

December 1998


common methods for minimizing the effects of bias are described in Appendix I. If the studyprovides evidence that the investigators reduced the effects of bias, the methodologic qualitygrade was advanced to the next highest level.

It should be noted that inclusion criteria could influence report findings. The inclusion criteriachosen for this report permit review of the best evidence available on the clinical use of FDGPET scans for selected conditions. These generally represent larger controlled studies publishedin the peer-reviewed literature. A limitation of this analysis is the potential language bias owingto including only English language articles. Thus, the reader should keep in mind that thefindings and recommendations are based only on evidence that meets criteria for inclusion in thereport.

VII. APPRAISAL OF THE LITERATURE

For this update, titles and abstracts of 474 references were screened. Sixty-four references weredetermined to be relevant, and their full text articles were reviewed for potential inclusion in thesystematic review. Additional articles were retrieved to provide background materials about thetechnology and selected clinical applications.

Forty-seven articles from the database searches and from end references of initially retrievedarticles met the inclusion criteria for review. Each included study was classified according toclinical condition and assigned to a diagnostic efficacy level as follows:

Efficacy level*

Head

& N

eck

Brea

st

Lung

sta

ging

SPN

Colo

rect

al

Alzh

eim

er’s

Technical 4 4 7 1 2 8Diagnostic accuracy 3 6 7 2 3 0Diagnostic thinking ? ?Therapeutic ? ?Patient outcomeSocietal

* Adapted from Fryback and Thornbury, 1991? Anecdotal data also presented in diagnostic accuracy studies.

In all oncology areas, higher levels of studies in the diagnostic test hierarchy supersededtechnical efficacy (feasibility) studies, represented the best evidence on the efficacy of FDGPET, and were summarized for this review. Technical efficacy studies are listed in thereferences. In Alzheimer’s disease, only technical efficacy studies met the inclusion criteria forreview.

All but one of the included studies were single-site studies classified as case series (Level Vevidence), representing a relatively weak study design that does not provide strong evidence ofeffectiveness. Case series contain useful information about the clinical course and prognosis ofpatients, can suggest relationships between interventions and outcomes, and can generate ideasfor further research. All studies used patients with no disease or with benign disease as internalcontrols.

December 1998


All included studies used dedicated PET systems. The TA Program identified only onepreliminary study using camera-based PET in oncology (Shreve, 1998). These authors comparedblinded readings of camera-based PET images, using attenuation-corrected dedicated PET as thestandard of reference, in 31 patients with known or suspected tumors. Accordingly, it did notmeet criteria for inclusion in this review. The results are summarized below.

Table 5: Summary of the Technical Efficacy of Camera-based PETin 31 Patients with 109 Lesions

Site Short-axis diameter (cm)Range, mean

# lesions detected oncamera-based PET

# lesions detected ondedicated PET

Lung 0.9-4.0, 2.7 13 14

Mediastinum 0.6-1.3, 1.0 5 15

Mediastinum 1.5-3.5, 2.2 15 16

Axilla 1.2-1.5, 1.3 5 9

Head and neck 1.1-2.4, 1.7 5 7

Abdomen 1.2-6.3, 2.8 6 26

Skeleton Not available, could not bedetermined 11 22

The authors concluded that camera-based FDG PET could depict many of the lesions depictedwith dedicated PET. Detection of lesions using camera-based PET was greatest in the lung andpoorest in the abdomen and in all sites, excluding the lungs, for tumors generally less than 1.5cm in short-axis diameter. The results of this preliminary study require valid estimates ofdiagnostic accuracy and marginal value using an appropriate reference standard in order toestablish camera-based PET as a diagnostic tool.

A. Data Synthesis

This report presents a qualitative overview to synthesize the best available evidence. Aquantitative synthesis (meta-analysis) was not attempted. The methodologicalweaknesses of case series, combined with present differences in design and analysisamong the eligible studies, argued against the validity and usefulness of pooling studyresults (Eysenck, 1994).

VIII. PUBLISHED FINDINGS

Background information on each clinical condition such as risk factors, diagnosis, alternativediagnostic modalities, staging, treatment and survival was described in detail in the first MDRCPET report (Flynn, 1996), and will not be presented here. A brief synopsis of updatedepidemiological information and an account of the potential role(s) for PET are presented foreach condition in addition to critical evaluation of the literature.

Epidemiological information for oncology conditions in this report is supplied by the AmericanCancer Society (American Cancer Society, 1998). Data on the veteran population are providedby the 1997 Annual Report of the Secretary of Veterans Affairs (West, 1998).

December 1998


Results are presented according to the potential role of PET in the management of each disease.Full data abstraction tables of the best evidence of PET for each cancer section are found inAppendix IV.

A. Head and Neck Cancer

This report will define head and neck cancer as the common squamous cell carcinomas ofthe oral cavity, nasal cavity and paranasal sinuses, pharynx, and larynx. Skin, brain,thyroid, and salivary gland tumors and the rare tumors of other histopathologic types(sarcomas and lymphomas) that can have primary sites in the head and neck will not bediscussed.

Approximately 41,400 new cases of head and neck cancer (3% of all incident cases of alltypes of cancer) and 12,300 deaths (2% of all cancer-related deaths) attributed to headand neck cancer are estimated for the United States in 1998. Within Veterans HealthAdministration malignant neoplasms of the lip, oral cavity, and pharynx (not larynx)accounted for 2,259 total discharges (0.3% of all discharges), with an average length ofstay of 18.5 days, in FY 1997.

Nearly one-third of patients with head and neck cancer has lower stage, confined diseaseat diagnosis. Most of the remaining patients have locally or regionally advanced diseaseincluding spread to lymph nodes in the neck. Less frequent is head and neck cancer thathas metastasized beyond the neck region (e.g., brain, lung, bone, or liver), at initialdiagnosis. Accordingly, standard therapy emphasizes local and regional approaches(surgery, radiation therapy, or combination) with curative intent.

Chemotherapy is increasingly being added to standard therapy to improve the outcome ofpatients with locally advanced disease (PDQ®; 1999). For resectable diseaseneoadjuvant chemotherapy is incorporated into many organ preservation strategies toshrink tumors preoperatively and may improve locoregional control. Organ preservationapproaches using concomitant chemotherapy with radiation are advocated in patientswith unresectable disease.

Diagnostic tests are used at several points in the initial work up and treatment of head andneck cancer. These include delineating disease at the primary site (including locatingunknown primary), identifying early nodal metastases, monitoring results of treatment,and identifying persistent and recurrent disease. CT and MRI have improved detection ofoccult cervical metastases for patients with head and neck cancer and subsequentmanagement of patients at high risk of cervical metastases.

However, improvements are still needed to define the primary site and in the other pointsin the work up mentioned above. The ability to assess response to chemotherapy-radiation organ preservation approaches is becoming increasingly more important, sincesurgical excision would be indicated in the event of treatment failure. The functionalinformation on glucose metabolism in head and neck tumors supplied by FDG PET couldbe clinically useful.

Table 6 depicts the study elements and Table 7 summarizes the data and quality ofindividual studies of PET using FDG in head and neck cancer.

December 1998


Detecting unknown primaries in patients with metastatic cervical nodes

Braams (1997), a small technical feasibility study, detected unknown primaries in13 patients with various histologic types of cervical metastases (see referencelist). They performed whole-body PET followed by endoscopy, after physicalexam and MRI and/or CT of the head and neck area failed to detect the primarytumor. PET identified the primary tumor in four (30%) patients and missed onesmall tumor (4mm) in another. Follow up over 18 to 30 months revealed noprimary lesion in the remaining eight patients. The authors suggested that PETmay be useful in guiding endoscopic exam and in identifying the primary site todirect more appropriate treatment.

Detecting primary disease

The MDRC Technology Assessment Program was unable to locate any PETstudies that met evidenced-based criteria for diagnosing primary disease.

Detecting cervical node metastases

Two studies in Table 6 met some of the evidence-based medicine criteria fordiagnostic test evaluations. Wong (1997) evaluated 16 patients, who had neckdissections, from a consecutive case series of 54 patients with known primarydisease or with suspected recurrence or residual disease. Data suggestcomparable performance of PET to anatomic imaging and improved performanceover clinical exam across patients with a range of stages, but a test of statisticalsignificance was not reported. In a small number of patients with occult nodal(N0) disease, PET did not perform as well as in patients with more advanceddisease. In addition to small sample size in the subgroup analyses, several aspectsof the study design were either unclear or not reported making the efficacy of PETdifficult to determine.

In a retrospective evaluation of 14 patients with N0 disease on clinical exam,Myers (1998) reported a trend of increased accuracy of PET, although notstatistically significant, over CT. PET combined with CT showed even greaterimprovement. Data were analyzed by dissected side and not by patient, andimportant study design elements were not reported.

December 1998


Monitoring treatment response

Lowe (1997) presented preliminary data on 28 consecutive patients with advancedhead and neck cancer, who were enrolled in a neoadjuvant organ-preservationprotocol, to assess PET in evaluating tumor response to chemotherapy. Themethods were reasonably well described, and the study met all evidence-basedmedicine criteria for diagnostic test evaluations. The data suggest good faceaccuracy of PET in distinguishing complete response from residual disease. Wideconfidence intervals reflect a small study size, and no comparison data werepresented.

The authors commented that while a positive PET scan may be indicative ofresidual tumor and warrant repeat tissue sampling or resection, a negative PETscan may also call for tissue sampling to rule out false negative results. They alsostated that PET may be used in situations when sampling bias is more likely, forexample, difficult access, questionable post-therapy biopsy results, or normal,reepithelialized appearance of the tumor site post-therapy.

Detecting recurrent disease

Wong and associates (1997) assessed PET prospectively for detecting bothprimary site recurrence in 12 patients and nodal recurrence in 13 post-treatmentpatients. PET showed high sensitivity in detecting recurrence at the primarysite, but they presented no comparison data. For detecting nodal recurrence,PET was more sensitive than CT or MRI, was equal to clinical exam, and hadsuperior specificity to both anatomic imaging and clinical exam.

December 1998


Table 6: Characteristics of Diagnostic Accuracy Studies of FDG-PET inPatients with Head and Neck Cancer

Studycharacteristics Lowe et al. (1997) Wong et al. (1997) Myers et al. (1998)

Perspective ? prospective prospective retrospective

Patient source Consecutive patients betweenDecember 1994 and May 1996with head and neck cancer:• 28 with stage III/IV who were

participating in a neoadjuvantorgan-preservation protocolusing Taxol and carboplatin

54 consecutive patients whopresented to head and neckclinics at two hospitals31 with primary disease (TI=2T2=10 T3=9 T4=10), 23 withsuspected recurrence or residualdisease)• 16 had neck dissections

116 patients diagnosed withhead and neck cancer, ofwhich 72 had biopsy-provenSCC and 26 underwent neckdissections:• 14 patients with N0 disease

(24 total neck dissections)on clinical exam

Extent of disease(# patients)

Stage III=3Stage IV =25

N0=8N1=4N2a=2N2b=2

Stage I=1Stage II=8Stage III=2Stage IV=3

Benignconditions 6 patients with pathologic

complete response None reported None reported

PET criteria forpositive result 1,2,or 3 on a 4 point scale Not reported Not reported

Contrast CTcriteria forpositive node

N/A Standard size and morphologicalcriteria used to assess nodaldisease on CT/MRI

Not reported

Interpretation • Blinded visual consensususing a before and aftercomparison format

• 4-point scale• two readers

Not reported Not reported

Gold standarddetermination(# patients)

Pathologic complete responseor residual disease based onpost therapy biopsies obtainedafter PET blinded to PET data(28)

• independent biopsy (16)• All suspicious areas of

aerodigestive tract werebiopsied

Histopathology for number ofnodes, presence ofmalignancy, and extracapsularspread (14)

Data analysis By patient By patient By dissection

Summary/Discussion

Since the 1996 MDRC PET report seven additional studies (three of diagnosticaccuracy) of PET in head and neck cancer were published, met the inclusioncriteria, and were reviewed. Evaluations of PET in head and neck cancer havefocused mainly on detecting cervical node metastases in patients with knownprimaries, diagnosing disease recurrence, and monitoring response to treatment.

PET has potential uses at several points in the diagnosis and management of headand neck cancer patients. An early step in defining these uses is obtainingestimates of diagnostic accuracy. Only Lowe and associates (1997) met allevidence-based medicine criteria for diagnostic test evaluations, and the methodswere reasonably well described. The two other studies did not report blinding oftest interpreters and had other methodologic limitations, which affect the validityof the results, and it was unclear whether PET was used in addition to, or as asubstitute for, other tests. All of the studies in Table 7 received low methodologicquality scores due to presence of significant bias, insufficient reporting and/orsmall sample sizes. The diagnostic accuracy estimates from these studies shouldbe interpreted cautiously.

December 1998


Information from a whole-body PET scan could have important treatmentimplications for patients with head and neck cancer. For example, identifying theprimary tumor site not detected by other modalities could alter treatmentplanning. If the primary is from the head and neck, it is potentially curable withsurgery and/or radiation therapy, whereas if the primary is located elsewhere, lesstoxic palliative treatment can be given. While there is a lower limit to the size oftumor that can be detected by PET, if validated in larger, rigorous studies, moreaccurate staging with PET could result in more appropriate treatment.

Minn et al (1997) (see reference list) assessed the feasibility of FDG uptake topredict cancer aggressiveness and survival. The results from 37 patients withprimarily advanced Stage III/IV disease suggested a correlation between FDGuptake and prognostic significance on univariate analysis but not on multivariateanalysis. Using FDG uptake to identify high-risk patients who would benefitfrom post-treatment surveillance requires further comparative study. Nonetheless,the wide range of primary sites and stages of head and neck cancer and theassociated wide range of site-specific treatment and outcomes would complicatesuch evaluations of PET.

Accurate diagnosis of disease recurrence is critical to the treating clinician. Withthe addition of chemotherapy to many organ-sparing protocols, the ability toaccurately assess nonsurgical treatment failure becomes increasingly moreimportant to judicious surgical salvage. For patients who become symptomatic orwho develop a mass during post-therapy surveillance, PET must be able todistinguish recurrence from treatment-related inflammation or fibrosis.

Goodwin (1998) suggested ways to improve such evaluations of PET that mayprovide more useful data to the treating physician. A prospective study of thesepatients, rather than a retrospective study of patients who had PET for variousreasons and at various times after treatment, would more appropriately address theclinical issue. Pretreating patients with steroids or antibiotics to reduceinflammation might enhance the positive predictive value of PET. Otherconsiderations include cost-effectiveness and capturing individual patient history,such as the timing of signs and symptoms after completion of therapy.

Controlled, prospective, blinded studies are needed to define the utility ofPET (either dedicated or camera-based systems) relative to other imagingmodalities in patients with head and neck cancer. Multiple sites may beneeded to accrue a sufficient number of patients. Results from this updatedliterature review confirm the conclusions and recommendations from thefirst report (see Preface).

December 1998


Met

hodo

logi

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D D D C D

Stud

y De

sign

Lim

itatio

ns

S,R,

W,t

S,r,W

,t,d

S,R,

W,t

S,R

S,R,

W,t

blinding — — — + —

Goldstandard H H H H H

Evid

ence

-bas

edM

edic

ine

Crite

ria

Comparisongroup + + + + +

Othe

r

Clini

cal e

xam

Se=5

8%

PET

+ CT

Se=8

6%Sp

=100

%PP

V=10

0%NP

V=91

%Ac

c=95

%

Clini

cal e

xam

Se=1

00%

Sp=6

0%

MRI

CT

CT +

MRI

Se=6

7%

Se=5

7%Sp

=90%

PPV=

80%

NPV=

75%

Acc=

76%

*

CT +

MRI

Se=7

5%Sp

=80%

Ope

ratin

g Ch

arac

teris

tics

PET

Se=6

7%

Se=7

8%Sp

=100

%PP

V=10

0%NP

V=88

%Ac

c=92

%**

(P=0

.11)

Se=1

00%

Se=9

0% (7

7-10

0%)

Sp=8

3% (5

3-10

0%)

PPV=

95%

NPV=

71%

Accu

arac

y=89

%

Se=1

00%

Sp=1

00%

N

12 p

ositiv

e ca

ses

4 ne

gativ

e ca

ses

9 po

sitive

disse

ction

s15

neg

ative

disse

ction

s

10 p

ositiv

e ca

ses

2 ne

gativ

e ca

ses

21 p

ositiv

e ca

ses

6 ne

gativ

e ca

ses

8 po

sitive

cas

es5

nega

tive

case

s

Stud

y

Won

g 19

97

Mye

rs 1

998

Won

g 19

97

Lowe

199

7

Won

g 19

97

Tabl

e 7:

Sum

mar

y of

Dia

gnos

tic A

ccur

acy

Stu

dies

of F

DG

-PE

T in

Hea

d an

d N

eck

Can

cer

H =

histo

logy;

F =

Follo

w up

; S =

sm

all s

ize;

R =

refe

rral b

ias;

W =

wor

k up

bias

; T

= te

st re

view

bias;

D =

diag

nosti

c re

view

bias

(upp

er c

ase

indica

tes

signif

icant

limita

tion;

lowe

r cas

e ind

icate

slim

itatio

n m

inim

ized

by s

tudy

des

ign,

pre

senc

e of

bia

s un

clear

, or s

mal

l effe

ct o

n op

erat

ing

char

acte

ristic

s)

Rol

e

Dete

ctin

gno

dal

met

asta

ses

Dete

ctin

glo

cal

recu

rrenc

e

Dete

ctin

gno

dal

recu

rrenc

e

December 1998


B. Breast cancer

The American Cancer Society estimates 180,300 new cases (178,700 women and 1,600men) of breast cancer will be diagnosed in 1998 in the United States. After a 4% per yearincrease in the 1980s, breast cancer incidence rates have leveled off in recent years toabout 110 cases per 100,000. An estimated 43,500 women and 400 men will die ofbreast cancer in 1998, making breast cancer the second major cause of cancer death inwomen. Mortality rates continue to decline, particularly in younger women, likely due toearlier detection and improved treatment.

In FY 1997, there were 1.2 million female veterans (4.8% of all veterans) living in theUnited States, and the percentage of females in the veteran population is expected toincrease. In accordance with the Women Veterans Health Program Act of 1992, HealthServices Research and Development supports research to increase outreach and access tohealth care and to explore health issues that affect many women, including breast cancer(Feussner, 1997). VHA has also established the Mammography Quality Standards Officeand has made available a nationwide toll-free mammography information line (888-492-7844) to expand mammography services to female veterans.

Potential applications for PET in breast cancer management were defined previously(Flynn, 1996):

• Non-surgical evaluation of breast disease;• Staging recurrent disease;• Quantifying tumor glycolytic rate as a prognostic factor;• Monitoring response to therapy;• Patient selection for axillary dissection and for preoperative therapy;• Screening in subgroups of women (eg, those with breast implants, with prior breast

radiotherapy, multiple breast masses and history of negative biopsy results, orseverely fibrocystic breasts).

Table 10 summarizes the data and quality of individual studies of PET using FDG inbreast cancer. Only studies of dedicated PET for non-surgical diagnosis of breastdisease, patient selection for axillary dissection, and staging recurrent/metastatic diseasemet the inclusion criteria for this review. Three studies evaluated quantitative indices ofFDG uptake as an indicator of prognosis. These studies were classified as technicalefficacy due to their preliminary nature and will be discussed in the Summary/Discussionsection.

Defining unknown primary disease

Palmedo (1997) prospectively compared PET to scintimammography (SMM)using 99mTc MIBI in the pre-surgical evaluation of 20 patients with 22 suspiciousprimary lesions detected by clinical exam or mammography. The mean lesionsize was 29mm (range 8-53mm), of which only 3 patients had lesions smaller than9mm. Quantitative analysis of tracer uptake was also performed to characterizedisease, but no cut-off value was defined prospectively. Anecdotal data suggestedthat PET was superior to SMM in detecting axillary lymph involvement, but

December 1998


neither test could determine extent of disease. The authors stressed that themenstrual cycle and age, which can alter MIBI uptake and FDG uptake,respectively, in normal tissue and the methods used to calculate FDG uptakecould affect test accuracy.

Detecting axillary lymph node involvement

The three studies in Table 8 met the inclusion criteria for review. Utech (1996),Crippa (1998), and Adler (1997) compared PET to axillary lymph node dissection(ALND) in patients with either suspected or confirmed breast cancer who werescheduled for axillary staging. Therapeutic decisions at surgery were based onclinical and routine imaging results, including mammography. PET was added inthe test sequence after the routine work up as a potential noninvasive method forstaging the axilla, the rationale being that a negative PET scan might obviate theneed for ALND in selected patients and, thus, decrease the morbidity and costsassociated with the procedure.

All were prospective studies, but only Crippa (1998) reported a consecutiveseries. The evidence for the use of PET in staging the axilla is confined to a selectgroup of patients with a high prevalence of malignancy and few benignconditions. The extent of axillary disease, reported in two studies, was limited topatients with metastases to ipsilateral axillary nodes. Crippa (1998) providedlimited evidence from small subgroups on the ability of PET to determine extentof disease, which is an important prognostic indicator; not surprisingly, PETsensitivity improved with more advanced disease.

Two studies used multiple readers to interpret PET images, but neither studyassessed interobserver variability. Of note, Adler (1997) used a higher dose oftracer and longer scanning times than were used in other studies. All studiesreported some evidence of blinding to the gold standard, but none met strictevidence-based criteria for blinding. Patient and disease characteristics, studydesign elements, and units of analysis varied across studies, and many studydesign elements were incompletely described or not reported, making the validityof these results difficult to assess.

December 1998


Table 8: Characteristics of Prospective Studies of Axillary Lymph Node (N)Staging With FDG-PET in Patients with Potentially Operable BreastCancer

Note: All studies included primary tumors of mixed histologies, primarily invasive ductal carcinoma.

Study Characteristics Utech et al. (1996) Crippa et al. (1998) Adler et al. (1997)Patient source 124 patients with newly

diagnosed and histologicallyproven breast cancer prior totherapy• 64 patients with

metastatic nodes• 60 w/ surgically negative

axilla• ? consecutive series

68 consecutive patients (72 totalaxilla) with palpable breast nodulesscheduled for surgery based onclinical andmammography/ultrasound results• 61 had ALND• no ALND in patients with benign

lesions (8) and in situ ductalcarcinoma (3)

From a larger prospectivestudy of PET, 50 patients with52 axillary dissections who metinclusion criteria:• age ≥ 30 years• ≥ 2 ALND within 3 mo. Of

PET scan• ≥ 10 nodes dissected• ability to fast ≥ 4 hours• ?consecutive series

Exclusion criteria(# patients)

Hyperglycemic patients None reported • History of ipsilateral axillarylymph node dissection

• Preoperative systemictherapy

• Primary tumor < 5mm• Uninterpretable PET scan

(2)Benign conditions ofbreast (#patients)

None • proliferative dysplasia withoutatypica (6)

• focal inflammation (2)

None

Primary tumor size(mean, range)

Reported as:<1cm=16>1cm=49>2cm=30>3cm=29

2.0 cm, 0.4-6.7cm Reported as:T0=1T1=31T2=17T3=3

Prevalence of confirmedN metastases(# positive patients/totalpatients)

44/124=35% 27/61=44% 20/52=38% (by axilla)

Extent of N metastases(# patients)

N0=79N1=43N2=2• one with bilateral disease

N0=36 (# axilla)N1a=21N1b=13N2=2

Not reported

Axillary node size Not reported Not reported Range <0.1cm-2.5cm

PET criteria for positivenode discrete focal uptake >

background focal uptake > surrounding tissue)increased FDG uptake andscan quality; scores ≥ 3=positive on a 5-point scale

Interpretation • 3 radiologists + 1 nuclearmedicine

• blinded to all data exceptprimary tumor

• # readers not reported• blinded to histopathology, but to

other information not reported

• two readers• independent, blinded to all

but axilla side• discrepancies resolved by

consensusGold standarddetermination(# patients)

• histology (104)• histology + follow up (20)• extensive nodal sampling

(average #/patient=19,range 7-46)

• histology (61)• Extensive nodal sampling

(average # /axilla=21, range 12-38)

• histology (50)• extensive nodal sampling

(average #/patient=17,range not reported)

Data analysis By patient By axilla By axilla

ALND=axillary lymph node dissection

Detecting recurrence and metastases

The two studies in Table 9 presented the best evidence on the use of PET to stagerecurrent disease and metastases in breast cancer patients.

December 1998


Table 9: Characteristics of Studies Using FDG PET to Stage Recurrent Diseaseand Metastases in Patients with Breast Cancer

Note: Both were retrospective studies.

Study Characteristics Bender et al. (1997) Moon et al. (1998)Patient source 75 patients with suspected recurrent or with

metastatic disease in undecided or equivocalcases• Includes results from CT/MRI• 63 patients had both PET and CT/MRI

data available for comparison• ?consecutive series

57 female patients (83 lesion sites) with a clinicalsuspicion of recurrence not resolved byconventional imaging:• who underwent primary surgery with or without

adjuvant chemo- or radiation therapy and• who were referred to the UCLA PET center from

October 1990 to October 1995• ?consecutive series


None reported • patients who underwent chemo-or radiationtherapy within 3 mo before PET

• lesions that were biopsied• lesions diagnosed with known disease

Benign conditions ofbreast (#patients)

None (# sites)• seroma (1)• muscle uptake (5)• thyroiditis (1)• radiation pneumonitis (1)• blood pool of great vessels (2)• osteoarthritis (1)• intestine (1)• unknown (6)

Primary tumor histology Well-differentiated ductal carcinoma (46)Infiltrating lobular carcinoma (10)

Not reported

Prevalence of confirmedlocal recurrence (#patients)

14/63=22% 29/57=51%

Prevalence of confirmedN metastases(# positive patients/totalpatients)

17/63=27% 8/26=31% (reported by lesion site)

Extent of M metastases(# patients)

• Bone (15)• Lung (5)• Liver (2)

• Bone (16)• Lung/Chest wall (7)• Liver (2)

PET criteria for positivelesion

4 point qualitative scale (intense, moderate,low, none)• Positivity criteria not defined

5 point qualitative scale• scores ≥ 3=positive

CT/MRI criteria forpositive lesion not defined N/A

Interpretation • 2 readers• independent• not blinded to other data

• 3 readers, discrepancies resolved by 4th reader• independent• blinded to histology but aware of suspicion of

metastasesGold standarddetermination(# patients)

• histology (71)• follow up (4)

• histology• lesion morphology on 2 or more conventional

imaging studies• ≥ 6 months of clinical and radiographic follow up

after PET

Data analysis By patient By patient and by lesion

Both studies were retrospective case series of patients with suspected recurrenceand/or metastases and equivocal findings after conventional imaging. PET wasused as a complement to conventional imaging. It was unclear whether thepatients in these studies represented consecutive case series. It should be notedthat Bender (1997) presented data on 75 patients, but only 63 patients hadinformation on both PET and CT/MRI for direct comparison. Few benign

December 1998


conditions were represented in either study. This may be an artifact of the workup, and the benign cases were likely identified prior to inclusion. Both studieshad a higher proportion of patients with metastases to the bone than to lung and/or chest wall, or liver. It was difficult to compare other characteristics of thepatient population across studies due to incomplete reporting or variations in theunits of analysis.

Both studies used qualitative scales to define lesions on imaging and multiplereaders to interpret the images. Moon (1998) presented some data oninterobserver variability. Moon (1998) met most of the evidence-based medicinecriteria for blinding, but Bender (1997) did not blind interpreters to other data.

Summary/Discussion

PET has several potential uses in the management of patients with breast cancer.Since 1996, four technical efficacy and six diagnostic accuracy efficacy studieswere published that met inclusion criteria for the review, representing the bestevidence supporting the use of PET in breast cancer management to date. No newstudies were identified that assessed the role of PET in evaluating response totreatment or screening in subgroups of women, such as women with radiodensebreasts or breast implants.

The evidence on the ability of PET to detect unknown primary disease for thisreport is limited to one small study comprising a select group with a highprevalence of malignancy and few patients with small primary lesions less than1cm. Limitations in study design and reporting suggest the preliminary nature ofthis study. The results should be confirmed in a larger group of patients with arange of tumor sizes, benign conditions and stages of disease. Newer PET modelswith higher resolution and availability of new dedicated breast PET scanners mayimprove detection of smaller lesions (Wahl, 1998).

The current best evidence, derived exclusively from case series of patients with ahigh prevalence of malignancy and with few benign conditions, does not supportthe routine use of PET as the initial test in patient selection for ALND. At facevalue, the operating characteristics from these studies suggest that PET has arelatively high sensitivity with a lower positive predictive value and acorrespondingly lower specificity with a higher negative predictive value ascompared to ALND. PET also yielded a fair number of false positives, many ofwhich could not be explained. Some of the more recent studies are larger, butmethodologic biases and incomplete reporting justified low methodologic qualityscores.

Variations in the characteristics of the study populations, scanning techniques,and in the units of analysis may affect the generalizability of these results,particularly to mammographically tested populations, which typically have alower prevalence of malignancy. Predictive values and other estimates ofdiagnostic accuracy should be interpreted with caution.

December 1998


ALND with histopathology of dissected nodes supplies critical information totreatment management, is currently recommended by the NCI for most patientswith Stage 1 or higher disease, but is associated with significant morbidity.Relative to other studies of screening and treatment options, published PET datato date are based on small numbers of patients. Moreover, the lower boundary ofresolution limits the ability of current PET modalities to detect tumors less than1cm in diameter. The consequences of false negative PET results in the absenceof ALND in patients for whom effective treatment is available should be avoided.

The potential for PET to visualize the internal mammary nodes (potentially N3disease) has been reported (Wahl, 1998). An NCI-sponsored multi-center trial isevaluating the accuracy of PET in staging the axilla and will include patients withN3 disease (See Section IX). Clinicians should await the results of this studybefore incorporating PET into routine clinical practice.

Likewise, the evidence on use of PET in detecting recurrent disease andmetastases and defining unknown breast disease is in its early stages. PET wastypically part of a testing sequence, but the marginal value of PET in the work upof these patients remains to be determined. The authors emphasized, and the TAProgram concurs with, the need for further studies to assess the clinical impact ofPET in the management of recurrent breast cancer.

Utech (1996), Crippa (1998), and Oshida (1998) (See technical efficacy list inReference Section) presented some evidence on the feasibility of usingquantitative FDG PET uptake by either the primary tumor or axillary lymph nodesas a prognostic indicator. Any attempt to correlate PET data with survivalrequires knowledge of the underlying characteristics of the study population andsufficient follow up time to track survival (Laupacis, 1994). The range of diseasestages and corresponding treatment options would further confound the results.Large, rigorous studies are needed to define the utility of PET as a prognostic test.

Controlled, prospective, blinded studies are needed to define the utility ofPET (either dedicated or camera-based systems) relative to other imagingmodalities in patients with breast cancer. Multiple sites may be needed toaccrue a sufficient number of patients. Results from this updated literaturereview confirm the conclusions and recommendations from the first report(see Preface).

December 1998


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December 1998


C. Non-Small Cell Lung Cancer

Bronchogenic carcinoma, classified as either small cell or non-small cell, comprises 95%of all primary lung cancers. This section will address only non-small cell varieties, asthey constitute the majority (75%) of all bronchogenic carcinomas and, when localized,have the potential for cure with surgical resection.

Bronchogenic carcinoma is the leading cause of cancer death in the United States. In1998 the American Cancer Society estimates 171,500 new cases of lung cancer and160,100 deaths from lung cancer. Malignant neoplasms of the bronchus and lungaccounted for 9,730 discharges (1.5% of all discharges) with an average length of stay of13.8 days within the Veterans Health Administration in FY 1997.

Non-small cell lung cancers (NSCLC) include adenocarcinoma (includingbronchioalveolar), squamous (or epidermoid) cell carcinoma, and large cell (includinglarge cell anaplastic) carcinoma. While 5-15% of NSCLCs are incidental findings on achest x-ray, the vast majority of patients have symptomatic, advanced disease at clinicalpresentation.

Initial diagnosis is based on complete history, physical exam, and chest x-ray. If canceris suspected, then staging is needed to assess the extent of local and distant disease.Stage of disease is the primary predictor of response to treatment and one of theimportant predictors of survival.

CT is the preferred diagnostic imaging test and is used at several points in themanagement of a patient with lung cancer: 1) to stage disease; 2) to evaluate treatmentresponse; and 3) to differentiate recurrent disease from fibrosis. Use of other diagnosticimaging technologies to stage lung cancer is circumscribed largely because of technicallimitations, availability, and cost.

CT provides morphologic (typically size) detail of the disease site. Accordingly, diseasestatus of mediastinal lymph nodes are classified according to size, with nodes greater than1 cm in diameter generally indicative of malignancy. This can be problematic, becausebenign lymph nodes may appear enlarged and micrometastases may appear normal onCT. Consequently, biopsy confirmation of the primary site and metastases is required todetermine the most appropriate treatment.

More accurate noninvasive methods for staging NSCLC are needed to minimize the useof invasive procedures for diagnosis and monitoring treatment response. To this end, themetabolic information provided by a PET scan may be useful. Several roles for PET instaging lung cancer have been identified in the literature:

• Defining unknown primary disease;• Detecting hilar and mediastinal metastases;• Detecting distant metastases;• Defining recurrence from fibrosis;• Analyzing tumor biology;• Monitoring response to therapy;

December 1998


• Predicting tumor response by measuring uptake of chemotherapeutic agents.

Tables 11 and 12 depict study characteristics and Table 13 summarizes the data andquality of individual diagnostic accuracy studies of FDG-PET in NSCLC that met theinclusion criteria for this review. Scores were further refined with pluses and minuses toreflect the degree to which investigators minimized the effect of these biases ondiagnostic accuracy results.

Defining unknown primary disease

Two studies met the inclusion criteria for the report. Guhlman (1997) andHagberg (1997) are relatively small retrospective surgical series with a highprevalence of malignancy in their respective cohorts. Both evaluated PET in thetest sequence after CT, but only Guhlman (1997) measured PET independently ofother tests in all patients. Neither study presented data comparing PET to CTalone. Both studies received low methodologic quality grades due to incompletereporting of methods and significant biases in study design, which may inflateestimates of diagnostic accuracy.

Detecting hilar/mediastinal adenopathy

Recent evidence on the use of PET in NSCLC emphasizes its staging potential.Six studies meeting the inclusion criteria presented evidence on the diagnosticaccuracy of PET in nodal (N) staging and are listed in Table 13. All enrolledpatients had suspected or biopsy-proven lung cancer. Data analyses included onlybiopsy-verified cases, implying a strong presence of work up bias across allstudies. All studies assessed the role of PET independently of CT in the work up;Vansteenkiste (1997) also assessed PET as an adjunct to CT.

Guhlman (1997) and Hagberg (1997) were small retrospective studies withseveral methodologic flaws. The remaining four studies were reported asprospective evaluations of PET. Ambiguous descriptions of study methodologycall into question the true, real-time prospective nature of three of them (Steinert,1997; Vansteenkiste, 1997; Sasaki, 1996). Of these three, Sasaki (1996) was themost methodologically flawed.

Bury (1997) presented the largest and the only discernibly true prospectiveevaluation of PET in staging patients with NSCLC. Steinert (1997) andVansteenkiste (1997) also presented notable attributes. These three studiesrepresent the strongest evidence on the use of PET in N staging patients withNSCLC and are presented in Table 11 for comparison.

December 1998


Table 11: Characteristics of Prospective Studies of Mediastinal Lymph Node(N) Staging With FDG-PET in Patients with Potentially OperableNSCLC

Note: All studies included mixed histologies, primarily squamous cell and adenocarcinoma.

StudyCharacteristics Bury et al. (1997) Steinert et al. (1997) Vansteenkiste et al. (1997)Patient source 141 consecutive patients who

presented between 9/94-10/96with new or suspected NSCLCbased on sputum cytology,needle biopsy, or flexiblebronchoscopy• 109 enrolled

62 surgical candidates withsuspected or proven NSCLCwho had PET between 2/94 and3/96• 47 enrolled

Unknown # patients who presentedbetween 9/95-4/96 with suspected orconfirmed NSCLC and who hadstandard M staging• 50 enrolled

Exclusioncriteria(# patients)

• poor physiologic status (22)• poor compliance or no

definitive diagnosis (11)

• prior neoadjuvant therapy• diabetes• inadequate CT (2)• distant metastases (8)• inadequate sampling (5)

• inoperable due to distantmetastases

• diabetes• treatment with oral corticosteroids• ischemic cardiomyopathy• direct mediastinal invasion of

primary tumor• obvious bulky mediastinal

adenopathiesPrevalence ofconfirmed Nmetastases(#N1-N3/#patients)

34/66=52% 29/47=62% 15/50=30%

Extent of Nmetastases(# patients)

N0=32N1=20N2=10N3=4

N0=18N1=16N2=7N3=6

N0=35N2=15

Benignconditions

• nonspecific inflammation=2• pneumonia=1• multinodular goiter=1• localized FDG uptake in

hepatic-splenic angle ofcolon=1

none reported none reported

PET criteria forpositive node

• moderate uptake: > 2Xuptake in contralateral orreference region

• intense uptake: markedlyhigher than reference region

• FDG uptake ≥ FDG uptake inbrain

• nodular appearance

Grades 4 and 5 on a 5-pointsemiquantitative scale

Contrast CTcriteria forpositive node

short axis diameter > 10 mm • short axis diameter > 10 mmexcept:

• upper paratracheal nodes >7mm short axis diameter

• infracarinal station > 11 mmshort axis diameter

maximal cross-sectional diameter ≥1.5 cm

Interpretation • independent, blind• consensus by 2 radiologists

and 2 nuclear medicine

• independent, blind• 1 radiology reader• 1 nuclear medicine reader

• independent, blind• one chest physician, one

radiologist• 2 nuclear medicine readers


• histology frommediastinoscopy (5),thoracotomy (51), both (10)

• radiologic follow up basedon CT or PET

• all accessible nodes atsurgery sampled

• extensive nodal sampling atthoracotomy of all identifiablenodes regardless of size onimaging

• mediastinoscopy (22) and/orthoracotomy (18)

• nodal sampling atmediastinoscopy (47) and atthoracotomy (49), fine needleaspiration (1)

• extent of sampling not reported

Data analysis correlated by patient correlated by nodal station correlated by patient

December 1998


Variations in study characteristics and units of analyses contributed to the rangeof reported estimates of diagnostic accuracy and differences in quality scoresacross studies. All studies had a significant degree of work up bias, whichcontributed to their low quality scores. All conducted varying degrees of nodalsampling, a means for minimizing diagnostic review bias, but the extent ofsampling varied and was not reported with sufficient detail to enable the reader toquantify the effect of this bias on diagnostic accuracy. Bury (1997) andVansteenkiste (1997) utilized multiple readers for blinded, independent imageinterpretation, but neither assessed interobserver variability.

Bury (1997) provided the strongest evidence to date on the diagnostic accuracy ofPET in N staging NSCLC. A comparison of PET to CT yielded comparableaccuracy estimates. The authors presented data on the impact of PET inmodifying treatment, but no methods for systematic assessment were described.Bias in the stated methods and in incomplete reporting of other critical designelements hindered evaluation of study validity in the other studies. None of thestudies assessed the incremental value of PET in the work up of NSCLC.

Detecting distant metastases

Studies in Table 12 met the inclusion criteria for review. Erasmus (1997)reported on 27 patients diagnosed with bronchogenic carcinoma and adrenalmasses detected by CT. Adrenal masses are common in patients with NSCLC,but in the absence of other extrathoracic metastases, they are likely to be benign.Diagnosis of many adrenal masses remains indeterminate after standard anatomicimaging (CT or MRI), and a biopsy is required before treatment can be planned.The rationale for using PET in this case is to improve the noninvasive diagnosticaccuracy, thus reducing the need for biopsy. Patients with normal FDG uptake inthe adrenals and no evidence of distant metastases might be considered eligiblefor curative resection.

The findings suggest that, as an adjunct to CT, PET can discern malignant frombenign adrenal masses using both visual and semiquantitative analyses. Resultsfrom this small preliminary study would need to be confirmed in larger,prospective studies to ascertain valid estimates of diagnostic accuracy and theadded value of PET in diagnosing adrenal masses in these patients.

Bury (1997) present the strongest evidence to date on the use of PET for Mstaging NSCLC. They compared PET independently to conventional imaging(chest CT, abdominal CT, and bone scintigraphy) for M staging 109 patients withnew or suspected NSCLC. The results suggest modest improvements insensitivity and negative predictive value for PET over conventional imaging. Theauthors reported that PET correctly changed M stage, as determined byconventional imaging, in 14% of the cases and modified therapy in 20% of thepatients, but the methods for assessing these changes were not described.

December 1998


Table 12: Characteristics of Prospective Studies of Distant Metastases (M)Staging With FDG-PET in Patients with NSCLC

StudyCharacteristics Bury et al. (1997) Erasmus et al. (1997)Patient source 141 consecutive patients with new or suspected

NSCLC who had PET and conventional imagingbetween September 1994 and October 1996:• 109 patients enrolled in study• 39 patients with 59 sites of confirmed distant

metastases

Unknown # consecutive cases presenting tothoracic surgery, oncology, or pulmonarybetween January 1993 and January 1996 with adiagnosis of bronchogenic carcinoma and anadrenal mass detected by CT• 27 patients with 33 adrenal masses enrolled in

study


• Poor physiologic status (22)• Poor compliance or no definitive diagnosis (11)

• Inability to obtain informed consent• Poor clinical status• Death

Patientcharacteristics

• 77 men, 32 women• mean age= 64 yrs (44-83 yrs)

• 19 men, 8 women• mean age= 57 yrs. (39-76 yrs)

Characteristics ofmetastases (#patients)

• NSCLC (109)• Mean diameter not reported

• NSCLC (24); Small cell (3)• Bilateral masses (6)• Mean diameter=3 cm (1-9cm)

Prevalence ofconfirmed distantmetastases

39 pts /109 pts=36% 23 sites /33 sites=70%

Locations of distantmetastases (# sites)

• Adrenal glands(10)• Nonregional lymph nodes (6)• Lung (10); Bone (13); Liver (18)• Pleura (1); Soft tissue (1)

Adrenal glands (27)

Benign conditions(# sites)

• Nonspecific inflammation (2)• Pneumonia (1)• Multinodular goiter (1)• Localized FDG uptake in hepato-splenic angle

of colon (1)

Not reported

PET criteria forpositive metastases

• Moderate uptake: > 2X uptake in contralateralor reference region

• intense uptake: markedly higher thanreference region

Positive activity= activity > background

CT criteria forpositive metastases

• Nodule characteristics not defined• Presence of clinical disease (symptomatic

patient, progression on imaging, abnormalbiochemistry) 6 months after imaging negativeimaging

Visual detection of mass, characteristics notdefined

Interpretation • Independent, blinded to all data excepthistology of primary tumor

• Consensus by 2 radiologists and 2 nuclearmedicine

• Independent, blinded to clinical and biopsyfindings

• 3 readers

Gold standarddetermination(# patients or sites)

• Biopsy (21)• Clinical and radiologic follow up (88)

• Percutaneous needle biopsy (11)• Growth characteristics on sequential CT

studies (16)• CT attenuation values < 10H (6)

Data analysis Correlated by patient correlated by site

December 1998


Summary/Discussion

Early studies of PET suggested several potential uses for PET in managingNSCLC (Flynn, 1996). Positive trends in Medicare and private sector coveragepolicies for PET in lung cancer staging continue to fuel interest in the use ofdedicated and camera-based PET as diagnostic tools. Since the first report, theTA Program identified 14 additional studies (7 of diagnostic accuracy) usingdedicated PET, which met the inclusion criteria for this report. There were threeareas in which potential uses for PET in NSCLC were studied: defining unknownprimary disease, detecting nodal metastases, and detecting distant metastaticdisease.

The best evidence on the diagnostic accuracy of PET in staging NSCLC suggestscomparable accuracy of PET to CT in nodal staging and slightly better sensitivity,negative predictive value, and accuracy of PET over conventional imaging instaging distant metastases (Bury, 1997). Significant methodological biases,incomplete reporting of critical design elements, and variations in studycharacteristics (e.g., lack of uniform criteria for defining positive results on PET)limit the validity of the included studies and warranted low methodologic qualityscores.

Appropriate use of the reference standard, or the “truth measure”, is among themost challenging aspects of these studies to assess. Diagnostic review bias isoften introduced, as biopsy sampling is rarely carried out independently ofimaging results (e.g., it would be impractical to blind the surgeon to imaging).Bury (1997) minimized the effect of diagnostic review bias in nodal staging byconducting extensive nodal sampling and in distant staging by confirming diseasestatus in all subjects using radiologic or clinical follow up or other confirmatorytests.

Imaging results are often used to determine which patients receive biopsyverification of mediastinal involvement (work up bias). To improve N stagingaccuracy several investigators advocated complementing the sensitivity of CTwith the high negative predictive value of PET. They reasoned that a negativePET scan following a positive or indeterminate CT scan would excludemediastinal metastases with a high degree of certainty and might obviate the needfor invasive mediastinal evaluation (e.g., mediastinoscopy).

The best evidence for PET’s N staging potential is confined to biopsy verifiedcases who had suspicious nodes on imaging. The size criteria for characterizingdisease on CT and the lower detectable limit of resolution with PET maymisclassify small tumor involvement, resulting in understaging. Failure toconfirm disease status through follow-up in patients with negative CT or PETresults may miss false negative results; failure to include the results in the analysiswould result in inflated sensitivity and negative predictive values. Accurate,robust negative predictive values from studies that reduce the effect of work upbias are critical to determining the utility of PET in mediastinal staging.

December 1998


Methodologically rigorous evaluations of diagnostic imaging, which reduced oraccounted for the effects of methodologic biases on diagnostic accuracy, havebeen published (See Appendix II). In particular, Webb (1991) of the RadiologicDiagnostic Oncology Group (RDOG) provides an excellent model for evaluatingdiagnostic imaging in staging NSCLC. From patient enrollment to data analysisthis rigorous evaluation offers extensive, detailed techniques for limiting themany biases inherent in diagnostic imaging studies. Incorporating study designelements from this model would strengthen the current best evidence for stagingNSCLC using PET.

The value of diagnostic PET cannot be determined solely on improved accuracyover existing modalities. PET must demonstrate changes in diagnostic certaintyand/or treatment planning or lower overall costs of patient management to justifyits role in the work up. It can be argued that the metabolic information from PETmay complement the information provided by conventional anatomic imaging andimprove staging accuracy. More accurate staging may lead to more appropriatetreatment planning. Studies included in this review reported anecdotal evidenceof changes in treatment planning attributable to PET, but the impact of PET ontreatment management was not systematically assessed, or reported as such.Furthermore, the range of stages and histologies of NSCLC and the associatedrange of treatments and outcomes would confound the effect of PET on outcomesof treatment, many of which are under investigation.

The TA Program concludes that the prevailing evidence does not support theroutine use of either dedicated or camera-based PET in lung cancer staging.Data from rigorous, prospective clinical trials are needed to determine theadded value of PET in the work up of NSCLC. Methodologically rigorousstudies of diagnostic imaging have been published in the peer-reviewedliterature. These studies may serve as models for guiding design of futurePET research. Review of the more recent evidence confirms the conclusionsfrom the first report.

December 1998


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Acc=

85%

Se=6

7%Sp

=63%

PPV=

43%

NPV=

81%

Acc=

64%

Se=6

5%Sp

=87%

(P<0

.05)

PPV=

61%

NPV=

89%

Acc=

82%

(P<0

.05)

PET

+ CT

Se=9

3%Sp

=70%

Se=9

3%Sp

=97%

PPV=

93%

NPV=

97%

Acc=

96%

Ope

ratin

g Ch

arac

teris

tics

PET

alon

e (9

5%CI

)

Se=9

4%Sp

=86%

Acc=

91%

Se=8

9% (7

2-96

%)

Sp=8

7% (7

1-97

%)

PPV=

89%

(72-

96%

)NP

V=87

% (7

1-96

%)

Acc=

88%

Se=8

0% (5

6-94

%)

Sp=1

00%

(73-

100%

)Ac

c=87

% (7

1-96

%) (

p<.0

2)

Se=6

7%Sp

=100

%

Se=8

9% (P

=0.0

066)

Sp=9

9%PP

V=96

%NP

V=97

%Ac

c=97

%

Se=6

7%Sp

=97%

PPV=

91%

NPV=

87%

Acc=

88%

Se=7

6%Sp

=98%

(P<0

.05)

PPV=

93%

NPV=

93%

Acc=

93%

(P<0

.05)

N 32 m

alig

nant

case

s14

ben

ign

case

s

44 p

ositiv

e no

dules

10 n

eg n

odule

s(in

49

patie

nts)

34 p

ositiv

e ca

ses

32 n

egat

ive c

ases

20 p

ositiv

e ca

ses

12 n

egat

ive c

ases

9 po

sitive

nod

es9

nega

tive

node

s(in

18

patie

nts

with

N2 d

iseas

e on

ly)

28 p

ositiv

e no

dal

statio

ns84

neg

ative

nod

alsta

tions

(in 4

7 pa

tient

s)

15 p

ositiv

e ca

ses

35 n

egat

ive c

ases

17 p

ositiv

e re

gions

54 n

egat

ivere

gion

s(in

unk

nown

#pa

tient

s)

Stud

y

Guh

lman

199

7

Hagb

erg

1997

Bury

199

7

Guh

lman

199

7

Hagb

erg

1997

Stei

nert

1997

Vans

teen

kiste

1997

Sasa

ki 19

96

Tabl

e 13

: Sum

mar

y of

Dia

gnos

tic A

ccur

acy

Stu

dies

of P

ET

and

Alte

rnat

ives

in S

tagi

ng L

ung

Can

cer

H =

histo

logy;

F =

Follo

w up

; S =

sm

all s

ize;

R =

refe

rral b

ias;

W =

wor

k up

bias

; T

= te

st re

view

bias;

D =

diag

nosti

c re

view

bias

(upp

er c

ase

indica

tes

signif

icant

limita

tion;

lowe

r cas

e ind

icate

s lim

itatio

n m

inim

ized

bystu

dy d

esign

, pre

senc

e of

bias

unc

lear,

or s

mall

effe

ct on

ope

ratin

g ch

arac

teris

tics)

Rol

e

(Som

e as

sess

edm

ultipl

e ro

les)

Defin

ing

unkn

own

prim

ary

dise

ase

Dete

ctin

gm

edia

stin

al/h

ilar

aden

opat

hy

December 1998


Met

hodo

logi

cQ

ualit

y G

rade

B/C C

Stud

y De

sign

Lim

itatio

ns

r,t,

S,r,d

blinding + +

goldstandard H

+ F

hist

olog

y +

CT fo

llow

up

Evid

ence

-bas

ed M

edic

ine

Crite

ria

comparisongroup

+ +in

tern

al

CT a

lone

(95%

CI)

(con

vent

iona

l im

agin

g*)

Se=8

2%Sp

=89%

PPV=

80%

NPV=

89%

Acc=

86%

PET

+ CT

Ope

ratin

g Ch

arac

teris

tics

PET

alon

e (9

5%CI

)

Se=1

00%

(91-

100%

)Sp

=94%

(86-

98%

)PP

V=90

% (7

8-97

%)

NPV=

100%

(95-

100%

)Ac

c=96

% (9

0-98

%)

Se=1

00%

Sp=8

0%

N 39 p

ositiv

e ca

ses

70 n

egat

ive c

ases

23 m

alig

nant

lesio

ns10

ben

ign le

sions

Stud

y

Bury

199

7

Eras

mus

199

7

Tabl

e 13

(con

t.): S

umm

ary

of D

iagn

ostic

Acc

urac

y S

tudi

es o

f PE

T an

d A

ltern

ativ

es in

Sta

ging

Lun

g C

ance

r

H =

histo

logy;

F =

Follo

w up

; S =

sm

all s

ize;

R =

refe

rral b

ias;

W =

wor

k up

bias

; T

= te

st re

view

bias;

D =

diag

nosti

c re

view

bias

(upp

er c

ase

indica

tes

signif

icant

limita

tion;

lowe

r cas

e ind

icate

s lim

itatio

n m

inim

ized

bystu

dy d

esign

, pre

senc

e of

bias

unc

lear,

or s

mall

effe

ct on

ope

ratin

g ch

arac

teris

tics)

Rol

e

(Som

e as

sess

edm

ultipl

e ro

les)

Dete

cting

dist

ant

met

asta

ses

* Bur

y et

al 1

997

defin

ed c

onve

ntion

al im

aging

as

ches

t CT,

abd

omina

l CT,

and

bon

e sc

intigr

aphy

December 1998


D. Solitary Pulmonary Nodules

Background information on solitary pulmonary nodules (SPN) is supplied by Lillingtonand Caskey (1993). A SPN is a single spherical lesion within the lung not associatedwith hilar enlargement or atelectasis and with a diameter generally less than 4.0 cm. TheAmerican Cancer Society reports that SPNs represent approximately 15% of all lungcancer diagnosed and estimates 25,725 new cases of malignant SPNs in the United Statesin 1998.

The differential diagnoses of a SPN include many malignant and benign processes. Themost common malignant forms are bronchogenic carcinomas. Reported prevalence ofmalignant SPNs range from less than 5% to greater than 70% because of differences inthe spectrum and severity of disease within each reported patient series. A malignantSPN represents a clinical stage I lesion, which is potentially curable with resection.Infectious granulomas represent the majority of benign processes and are causedpredominately by coccidiomycosis, histoplasmosis, and tuberculosis.

The following risk factors directly correlate with the probability of cancer in patients witha SPN: 1) patient’s age; 2) smoking history; 3) antecedent malignancy; 4) stability oflesion size on chest x-ray for 2 years; 5) absence of benign patterns of calcification withinthe nodule; and 6) nodule morphology (size and edge characteristics on CT). Thebaseline prevalence of malignancy in the study population may suggest the likelihood ofa malignant SPN. Exposure to benign diseases such as tuberculosis or a history ofresidence in areas endemic for coccidiomycosis or histoplasmosis will suggest a lesserlikelihood, but not rule out, malignancy.

Following clinical exam and chest radiography, the standard radiologic method of choicefor evaluating SPNs is CT. CT provides information on the location and morphology ofthe nodule and can be used to guide biopsy procedures. Iodinated contrast material andhigh resolution CT densitometry may be used to enhance the differential diagnosis.However, limitations in the use of CT have been reported. Many SPNs are classified as“indeterminate” after CT and warrant invasive biopsy confirmation to determine theappropriate therapeutic course.

FDG PET has been proposed as a potential solution for improving the noninvasivedifferential diagnosis of SPNs, thereby reducing the need for higher risk invasive biopsysampling and the associated morbidity and costs. Current evidence from this reviewsupports the complementary use of PET after CT in the work up of patients with nodulediameters less than 3 cm or 4 cm, i.e., those nodules most likely to be indeterminate.

Table 14 displays the attributes of each study to highlight the variations in study qualityand in criteria relevant to the applicability of the results. Table 15 summarizes the dataand quality of individual diagnostic accuracy studies of FDG PET in SPNs.

Characterizing indeterminate solitary pulmonary nodules

December 1998


Two studies met the inclusion criteria for this report. Dewan (1997) conducted aretrospective single-site study of indeterminate SPNs in 52 consecutive patients,who underwent PET between April 1990 and February 1994. They comparedPET with and without standard criteria (clinical and radiologic data) usinglikelihood ratios1 in Bayesian analysis to predict the probability of cancer in aSPN. Using sensitivity and specificity derived from this patient group, theauthors determined that PET alone was the best predictor of cancer.

However, biases in study design and violation of the assumption of conditionalindependence between tests in the testing sequence, a requirement of Bayesiananalysis, preclude drawing definitive conclusions regarding the accuracy of PETand its contribution to diagnostic certainty in these patients. Moreover, the impactof PET on treatment planning was not assessed. It is also important to note thatmany of these patients may have been included in studies assessed in the 1996report.

Lowe (1998) conducted a multi-site study of radiologically indeterminate SPNs in105 consecutive patients, who underwent imaging between October 1993 andAugust 1994. The study population included a broader range of benignconditions and nodule sizes compared with other published studies for thisindication, reflecting the advantages of multi-site design. The authors presented avery detailed description of their blinding procedures and were the onlyinvestigators to calculate interobserver variability in visual analysis. From thestated methods, it is unclear whether they collected patient data in a “real-time”prospective fashion or retrospectively from surgical series.

These authors calculated likelihood ratios overall and for each subgroup. Thelikelihood of cancer was consistently higher using quantitative analysis overvisual analysis. Except for specificity in SPNs ≤ 3cm in diameter, there were nosignificant differences between visual and quantitative analyses in the otherdiagnostic accuracy measures across subgroups. Small sample sizes in thesubgroups likely contributed to the failure to detect any significant differences.Interobserver variability was very low (kappa=0.95), indicating goodreproducibility of image interpretation.

1 Likelihood ratio, expressed as Sensitivity/1-Specificity, is a measure of accuracy that indicates by how much adiagnostic test result will raise or lower the pretest probability of disease, thereby increasing the certainty about apositive or negative diagnosis.

December 1998


Table 14: Characteristics of Studies Using FDG-PET of Patients withRadiographically Indeterminate Solitary Pulmonary Nodules

StudyCharacteristics Dewan et al. (1997) Lowe et al. (1998)Perspective Retrospective Prospective (?not real-time)

Patient source

52 consecutive patients who underwent PETbetween April 1990 and February 1994• included 3 with extrathoracic malignancy

Multisite study of 89 of 105 consecutive patients whounderwent imaging between October 1993 and August1994


• Cavitary or calcified nodules• Nodule size > 3cm• Age ≤ 30 years• # patients not reported

• no definitive histologic confirmation (8)• 4 not classified as radiographically indeterminate SPN

(4)• no available CT scans (2)• nodule size < 0.7cm or > 4.0cm on CT(? # pts.)

Patient demographics

• 43 men (83%)• mean age ± SD=63.6±11.3 years• 41(79%) current smokers• 52% ≥ 20 cigs/day

• 61 men (69%)• mean age ± SD=63±9.5 years• smoking status not reported

Prevalence ofmalignancy 37/52=71% 60/89=67%

Nodule size in cm(%malig. pts. vs.%benign pts.)

≤ 1.0= 19% vs. 47%1.1-2.0=51% vs. 40%2.1-3.0=30% vs. 13%

0.7-1.5= 25% vs. 66%1.6-3.0=60% vs. 24%3.1-4.0=15% vs. 10%

Nodule Morphology(%malig. pts vs. %benign pts.)

Edge characteristics reported:• Sharp, smooth=14% vs.20%• Lobulated=30% vs. 40%• Slightly irregular w/ few spiculations=38% vs.

33%• Grossly irregular and spiculated=19% vs. 7%

Not reported

Benign conditions(#pts.)

• histoplasma granuloma with active inflammation(2)

• other conditions not reported

• granuloma (7), coccidiomycosis (4), benign cellulardebris (4), nonspecific inflammation (3), necrotizinggranuloma (3)

• fibrosis (1), hemangioma (1), aspergillosis (1),metaplasia (1)

PET criteria forpositive node

focal FDG uptake > surrounding lung tissue, butmore than mild intensity

• focal uptake > mediastinal blood pool structures(qualitative)

• SUV> 2.5 (semiquantitative)CT criteria for noduleedge

based on 4-type scale to reflect degree ofspiculation and irregularity not specified to image interpreters

Interpretation of PET

• qualitative• 1 reader blinded to histology• blinding to clinical and radiologic information

varied

• semiquantitative using SUV• independent qualitative analysis using 2 readers

blinded to clinical , imaging, and histopathologic datareached by consensus

• readers interpreted studies with which they were notinvolved to ensure blinding

• interobserver variability calculated

Interpretation of CT• independent• 2 readers blinded to clinical diagnosis• consensus reading

• independent interpretation by > 1 reader blinded toclinical, PET, or histopathologic results

• qualitative interpretation as benign or indeterminateGold standarddetermination(# patients)

thoracotomy (36), mediastinoscopy (3),bronchoscopy (3), needle lung biopsy (9), follow-up imaging for > 2 yrs (1)

TTNA (29) or surgery (60)

Data analysis By patient By patient

TTNA=Transthoracic Needle Aspiration

December 1998


Summary/discussion

Since the 1996 report, three additional studies using dedicated PET in diagnosingsolitary pulmonary nodules met the inclusion criteria for review. One was atechnical feasibility study, and two were of diagnostic accuracy assessing PET inthe test sequence after CT but prior to any histologic confirmation of disease.Both had significant biases in study design that warranted low methodologicquality scores and call for caution in generalizing these results to otherpopulations.

Most false negative results reported in the PET literature are caused by smallnodules with diameters commonly <1 cm that approach the resolution limits ofthe camera. Both studies reported false negatives comprising a variety of non-small cell cancers with diameters ranging from 1 cm to 2.5 cm. Moreover, theimpact of PET on treatment planning, particularly the decision to proceed tosurgery, was not systematically assessed.

One of the deficiencies outlined in the first report is the relatively low number ofpatients and a correspondingly narrow spectrum of benign conditions representedin the study base. Lowe (1998) presented the largest and only multi-site study ofPET in diagnosing SPNs. Multi-site trials have the advantage of recruiting largernumbers of patients with a comprehensive array of malignant and benignconditions that are needed to apply the results to other populations. The detaileddescription of the blinding procedures used in the study may serve as a model forfuture studies of PET.

Both studies derived likelihood ratios (LR) to quantify the importance of the PETresults in the work up of SPNs. As with predictive values, LRs are more usefulaccuracy measures to a clinician than sensitivity and specificity. LRs are used tocalculate the probability of disease given a test result. They are independent ofdisease prevalence in most circumstances, but differences in case mix andmethodologic biases can influence their validity (Gurney, 1993).

For example, the prevalence of malignancy in SPNs is lower in communityhospitals than in most surgical series or in tertiary care facilities, where most PETscanners are found. Areas that experience a higher prevalence of particularbenign conditions may encounter more false positive results on PET. A studywith too few patients with benign nodules may overestimate specificity andinflate the negative LR; presence of methodologic biases may overestimatesensitivity and inflate the positive LR. In both studies the inclusion criteriafavored a higher proportion of patients with malignancies and with too few benignconditions to offset the influence on specificity. Thus, rigorous study of a largernumber and range of patients with a mix of diseases is needed to derive validlikelihood ratios for PET in patients with SPNs.

December 1998


Met

hodo

logi

cQ

ualit

y G

rade

D D

Stud

y De

sign

Lim

itatio

ns

S,R,

W,T

,d

s,r,W

,d

blinding

varie

d

+(fo

r visu

alan

alys

ison

ly)

goldstandard H

+ F

H

Evid

ence

-bas

ed M

edic

ine

Crite

ria

comparisongroup

+

+

PET

afte

r CT

Sem

iqua

ntita

tive

anal

ysis

(95%

CI)

Se=9

2% (8

2-10

0%)

Sp=9

0% (7

9-10

0%)

Acc=

91%

LRma

l=9.

0LR

ben=

0.09

Ove

rall v

alues

repo

rted

Ope

ratin

g Ch

arac

teris

tics

PET

afte

r CT

Visu

al a

naly

sis

(95%

CI)

Se=9

5%Sp

=87%

Acc=

92%

LRma

l=7.

11 (6

.36-

7.96

)LR

ben=

0.06

(0.0

5-0.

07)

Ove

rall v

alues

repo

rted

Se=9

8% (9

5-10

0%)

Sp=6

9% (5

7-81

%)

Acc=

89%

LRma

l=3.

0LR

ben=

0.02

Ove

rall v

alues

repo

rted

N 32 m

alig

nant

case

s14

ben

ign

case

s

60 m

alig

nant

case

s29

ben

ign

case

s

Stud

y

Dewa

n 19

97

Lowe

199

8

Tabl

e 15

: S

umm

ary

of th

e D

iagn

ostic

Acc

urac

y an

d D

iagn

ostic

Thi

nkin

g E

ffic

acy

Stu

dies

of P

ET

in In

dete

rmin

ate

S

olita

ry P

ulm

onar

y N

odul

es (S

PN

)

H =

histo

logy;

F =

Follo

w up

; S =

sm

all s

ize;

R =

refe

rral b

ias;

W =

wor

k up

bias

; T

= te

st re

view

bias;

D =

diag

nosti

c re

view

bias

(upp

er c

ase

indica

tes

signif

icant

limita

tion;

lowe

r cas

e ind

icate

s lim

itatio

nm

inim

ized

by s

tudy

des

ign,

pre

senc

e of

bia

s un

clear

, or s

mal

l effe

ct o

n op

erat

ing

char

acte

ristic

s)

Rol

e

Defin

ing

inde

term

inat

eSP

N

December 1998


Once valid LRs are derived, they may be used to estimate the odds that a patienthas a cancer, given the PET result. Any attempt to use LRs in evaluating the oddsof cancer after PET requires: 1) knowledge of the odds of cancer before PET, and2) that the PET results were derived independent of the other test results. Inneither study were both conditions satisfied, and the influence of PET ondiagnostic certainty and subsequent treatment planning could not be determined.

Rigorous studies of patients comprising a range of pre-PET probabilities ofmalignancies are needed to assess the diagnostic accuracy and contributionof either dedicated or camera-based PET to the work up of solitarypulmonary nodules. Multiple sites may be needed to accrue a sufficientnumber and array of patients. Results from this review update confirm theconclusions and recommendations from the first report.

The Cooperative Studies Program of the VHA Office of Research andDevelopment has funded a multi-year cooperative study to determine theefficacy of FDG-PET in defining solitary pulmonary nodules (See SectionVIII). Results from this study should address the shortcomings of theexisting literature.

E. Colorectal Cancer

Colorectal cancer is the third leading cause of death among men and women, representinga significant public health problem in the United States. Colorectal cancers account forapproximately 11% of new cancer diagnoses. Death rates from colorectal cancer havefallen 25% for women and 13% for men during the past 20 years, reflecting a decreasingincidence of new cancer cases and increasing survival rates.

An estimated 131,600 cases and 56,500 deaths are attributable to colorectal cancer in theUnited States in 1998. An estimated 1 million veterans over the age of 50 will developcolorectal cancer over the remainder of their lives and nearly 433,000 will die from it(Wingo, 1995; Brown, 1996). Within the Veterans Health Administration, malignantneoplasms of the digestive organs and peritoneum (which include colorectal cancer)accounted for 8,280 discharges (1.2% of all discharges) with an average length of stay of15.7 days in FY 1997.

Winawer (1997) reported the following risk factors for colorectal cancer: age over 50years; a history of adenomatous polyps; a history of curative intent resection of colorectalcancer; inflammatory bowel disease; and familial colorectal cancer, adenomatouspolyposis, or hereditary nonpolyposis colorectal cancer.

Nationally, the estimated relative five-year survival rate among veterans is approximately40%, substantially lower than estimates from the general population of 62% (colon) and59% (rectum). In VA, the Office of Research and Development (ORD)’s EpidemiologicResearch and Information Center in Durham, North Carolina is conducting a four-yearinitiative to identify factors that may explain the worsened prognosis among veterans,and that may be responsive to intervention (Provenzale, 1998). ORD is also conducting alarge prospective study of risk factors and/or detection of altered cell proliferation for

December 1998


large colonic adenomas in asymptomatic subjects; the results will have importantimplications for colon cancer screening (Lieberman, 1998).

Data on management of colorectal cancer are from the National Cancer Institute’sPhysician Desk Query (PDQ) system retrieved in October 1998. The most prevalenthistologic type of colorectal cancer is adenocarcinoma. Metastases to the liver,abdominal cavity, and extra-abdominal areas at initial diagnosis are common, as isrecurrent disease after surgical resection of the primary tumor. Prognosis andmanagement depends on the depth of tumor penetration into the bowel wall and thepresence of both regional lymph node involvement and distant metastases (staging).

Surgery is the primary therapy for colorectal cancer, and for cancers that have notmetastasized, it is frequently curative. Many patients with confined recurrent disease orwith metastases limited to the liver or lungs may also be amenable to resection.However, the high rate of recurrence and a troubling overall five-year survival rate callfor more appropriate selection of patients who may benefit from surgical resection. Themorbidity and costs associated with surgery for patients who do not have genuinelyresectable recurrent tumor could be avoided by improved methods of tumor detection.

Stotland (1997) reviewed several imaging modalities commonly used to stage anddiagnose colorectal cancer. The most common modalities include CT, MRI, endoscopicultrasonography (EUS), and transabdominal ultrasonography. The popularity of EUS, inparticular, has grown in recent years for its ability to image the depth of tumorpenetration into the bowel wall and regional lymph node involvement. MR endorectalcoils or ultrasound probes may be used to image rectal lesions. However, all structuralimaging modalities are circumscribed in their ability to determine the presence and extentof disease and disease recurrence. Information from newer modalities, such asintraoperative ultrasonography, immunoscintigraphy, arterioportography, and PET, mayincrease the accuracy of staging and detecting recurrence.

Potential roles for PET in colorectal management have been identified in the literature:

• Pre-operative staging, including diagnosing presence and extent of liver metastases,and;

• Post-operative monitoring of recurrent disease.

Five studies met the inclusion criteria for review. Of these, two were technical efficacystudies and are listed in the reference section. Table 16 lists the characteristics of tworetrospective case series and one prospective case series of diagnostic accuracy, andTable 17 summarizes the data and quality, representing the best evidence for the use ofPET in managing patients with colorectal cancer. All studies presented some anecdotalevidence of therapeutic efficacy.

Preoperative staging of colorectal cancer

The TA Program identified one small uncontrolled, unblinded technical feasibilitystudy of PET for staging initial primary colorectal cancer (Abdel-Nabi, 1998).

December 1998


No diagnostic efficacy studies of staging primary colorectal carcinomas usingPET were identified for review.

Four relatively small case series presented evidence on the use of PET in patientswith suspected recurrent colorectal cancer, of which Ruhlmann (1997) was aretrospective technical feasibility study. The three remaining case series arediagnostic accuracy studies. Ogunbiyi (1997) and Flanagan (1998) areretrospective analyses from the same institution with overlapping studypopulations. Ogunbiyi (1997) studied 58 patients with a high suspicion forrecurrence, including some with advanced primary disease, based on clinicalsymptoms, elevated plasma carcinoembryonic antigen (CEA) concentration,and/or CT findings. Flanagan (1998) assessed the ability of PET to detectrecurrence in 22 asymptomatic patients with a post-operative elevated CEAconcentration and normal clinical and radiologic findings.

Delbeke (1997) presented the only prospective comparison of PET to CT and CTarterial portography (CTAP) in detecting liver and extrahepatic metastases in 52patients with suspected recurrent colorectal cancer. This is likely a continuationof an earlier, smaller study from the same institution (Vitola, 1996), which wasreviewed in the previous 1996 MDRC technology assessment.

In all studies PET was performed as an adjunct to the routine clinical andradiologic work up, but the initial work up was not described in detail. Currentevidence suggests that, when PET is added to the work up, there is improvedsensitivity in distinguishing recurrence from post-surgical changes anddocumenting the presence and extent of liver and more distant metastases.However, the methodologic shortcomings in these studies limit the validity ofthese estimates. Predictive values may be subject to considerable referral biasowing to the high suspicion for malignancy in the study population. Lack ofdocumentation of disease severity and underlying condition of the liver,completeness of the work up prior to PET, and blinding further hindersassessment of these results.

December 1998


Table 16: Characteristics of Studies of Pre-operative Staging With FDG-PET inPatients with Suspected Recurrent Colorectal Cancer

StudyCharacteristics Delbeke et al. (1997) Ogunbiyi et al. (1997) Flanagan et al. (1998)

Perspective Prospective Retrospective Retrospective

Patient source 52 patients presented on 61occasions with suspectedrecurrent carcinoma• Consecutive series

58 patients who had PETbetween 1/91 and 1/95 withsuspected recurrent (n=47) oradvanced primary (n=11)disease

• ? Consecutive series

22 of 128 patients with history ofcolorectal cancer, who underwentPET from 6/93 to 6/96

• ? Consecutive series

Inclusion criteria • Elevated CEA levels orabnormal CT

• Abdominal CT (n=48);CTAP (n=40); or both(n=29)

• High clinical suspicion andequivocal or positive CTfindings (n=39)

• Elevated CEA levels withnormal CT (n=19)

• Normal CEA levels after initialresection

• Plasma CEA level > 5.0 ng/ml(mean 25 ng/ml), normalimaging studies, endoscopy,and physical exam on routinefollow-up

Patientcharacteristics

• 31 men, 21 women• Mean age 63 ± 11 yrs

• 33 men, 25 women• Mean age 60 yrs. (23-81 yrs)

• 17 men, 5 women• Ages 17-84• Primary site: colon (9), rectum

(10), rectosigmoid (2), appendix(1)

Extent of disease(#patients)

• Liver metastases (45)• Extrahepatic disease (26,

including 16 with liver mets)

• Primary disease or localrecurrence (21)

• Liver metastases (23)• Extrahepatic metastases (20)

• Stage B (10)• Stages C (5), C1 (2), C2 (3),• Stage D (2)

Benignconditions(# patients)

• Normal liver (7)• Post-surgical site (8)• Local fibrosis (2)• Resolving abscess (1),

hepatic cyst (1), hematoma(1)

Not reported in reproducibledetail

Not reported

PET criteria forpositive site

• Not specified for qualitativePET

• Cut-off not specified forsemiquantitative analysis

• Malignancy=FDG uptakemoderately or markedlyintense;

• Benign=no or mild uptake, orif abnormality identified onother imaging for which nocorresponding abnormalitywas present on PET

Not specified

Contrast CTcriteria forpositive site

• Not specified for surgicalcases

• In nonsurgical cases, anincrease in lesion volume >20% on serial scans

Not specified Not specified

CTAP criteria forpositive site

• Not specified for surgicalcases

• In nonsurgical cases, anincrease in lesion volume >20% on serial scans

N/A N/A

Interpretation • 2 readers for PET , 2readers for CT and CTAP,

• Independent, qualitativePET blinded to otherimaging results

• Semiquantitative PET SURcalculations excludedlesions < 1 cm in diameter

• Qualitative PET interpretedwith access to CT results

• Two readers• CT interpreted in “routine

clinical fashion”

• Qualitative PET scansinterpreted with access to CTresults

• Consensus of at least tworeaders

• CT interpreted in “routine clinicalfashion”


• Clinical or radiologic followup (n=17)

• Histopathology obtainedsurgically (n=44)

• Percutaneous fine needleaspiration (n=2)

• Nonresected lesions=surgical exam andintraoperative ultrasound(unknown #)

• Surgery, histology, or both(n=40);

• Clinical and radiologic followup (n=16); autopsyreports(n=2)

• All patients followed for atleast 12 months after PET oruntil death

• Pathology (n= 9)• All patients had radiologic and

clinical follow up ≥ 6 months

Data analysis By lesion site By patient By patient

December 1998


Each study presented some evidence on changes in patient managementattributable to PET, but the methods for assessment were not reported. Theevidence suggests that adding PET to the work up may help optimize treatment(e.g., improve patient selection for curative surgery) by documenting the presenceor absence of hepatic or more distant metastases. These data would need to beconfirmed in much larger prospective studies designed to systematically assessthe incremental value of PET against the many other available imaging modalitiesused in the work up of colorectal cancer.

Postoperative monitoring recurrent disease

The TA Program did not identify any studies in the published literature thataddressed the role of PET in routine postoperative monitoring of patients forrecurrent disease.

Summary/Discussion

Since the first report, five additional studies using dedicated PET in themanagement of colorectal cancer met the inclusion criteria for review. The bestevidence to support the use of PET in colorectal cancers are three reported caseseries of diagnostic accuracy, of which two were retrospective studies from thesame institution with overlapping study populations. All assessed the ability ofPET as an adjunct to CT and other diagnostic tests to stage potentially operablepatients with a high suspicion of recurrent disease; the one prospective case seriesalso included patients with advanced primary disease. No diagnostic accuracystudies of PET to stage early, primary disease were identified.

Current evidence suggests that to further define recurrent disease, PET added afterCT may offer improved sensitivity over CT alone. The absolute sensitivity ofimaging modalities in detecting hepatic and more distant metastases is difficult todetermine (Stark, 1987). Work-up bias is present when results from PET and/orother imaging tests under evaluation are used to direct biopsies to confirmsuspicious liver lesions or to direct the choice of the most appropriate referencemeasure. Biopsy resection, while not entirely perfect, is a very accurate referencemeasure.

All authors attempted to offset work up bias by confirming disease in unresectedpatients using less perfect truth measures, such as clinical and radiologic follow-up, surgical exam and palpation, and intraoperative ultrasound. Although usingthese truth measures may not adequately identify the number of false negatives,they are reasonable alternatives and are preferred over nothing. The extent towhich work up bias can be eliminated in this clinical setting is limited.

All of these studies had significant methodologic biases and insufficient reportingof fundamental design elements that preclude definitive assessment of studyvalidity. The accuracy estimates from these studies should be interpreted withcaution.

December 1998


Met

hodo

logi

cQ

ualit

y G

rade

D D D D D

Stud

y De

sign

Lim

itatio

ns

S,R,

w,T

,d

S,r,T

,D

S,r,W

,t,d

S,R,

w,T

,d

S,r,w

,t,d

blinding

parti

al

parti

al

goldstandard

Surg

, H &

F

H &

F

Surg

, int

ra-

oper

ativ

eUS

, H &

F

Surg

, H, F

& au

tops

y

H &

F

Evid

ence

-bas

ed M

edic

ine

Crit

eria

comparison group + + + + +

CT a

lone

Se=5

7%Sp

=81%

PPV=

71%

NPV=

70%

Acc=

70%

Se=8

1%Sp

=60%

Acc=

78%

Se=7

4%Sp

=86%

PPV=

77%

NPV=

83%

Acc=

81%

Se=7

4%

CTA

P

Se=9

7%Sp

=5%

Acc=

80%

Ope

ratin

g Ch

arac

teris

tics

PET

afte

r CT

Se=9

0% (P

=0.0

08)

Sp=1

00%

PPV=

100%

NPV=

93%

Acc=

96%

Se=1

00%

Sp=7

1%PP

V=89

%NP

V=10

0%

Se=9

1%Sp

=95%

Acc=

92%

Se=9

6% (P

=0.0

2)Sp

=100

%PP

V=10

0%NP

V=97

%Ac

c=98

%

Se=1

00%

N 21 re

curre

nt c

ases

26 n

o re

curre

nce

15 re

curre

nt c

ases

7 no

recu

rrenc

es

104

mal

igna

nt le

sions

23 b

enign

lesio

ns

in 45

pat

ients

23 c

ases

with

dise

ase

35 n

o di

seas

e

34 m

alig

nant

lesio

ns5

benig

n les

ions

in 26

pat

ients

Stud

y

Ogu

nbiyi

(199

7)

Flan

agan

(199

8)

Delb

eke

(199

7)

Ogu

nbiyi

(199

7)

Delb

eke

et a

l.(1

997)

Tabl

e 17

: S

umm

ary

of D

iagn

ostic

Acc

urac

y S

tudi

es o

f FD

G-P

ET

in C

olor

ecta

l Can

cer

H =

histo

logy;

F =

Follo

w-up

; S =

sm

all s

ize;

R =

refe

rral b

ias;

W =

wor

k up

bias

; T

= te

st re

view

bias;

D =

diag

nosti

c re

view

bias

(upp

er c

ase

indica

tes

signif

icant

limita

tion;

lowe

r cas

e ind

icate

slim

itatio

n m

inim

ized

by s

tudy

des

ign,

pre

senc

e of

bia

s un

clear

, or s

mal

l effe

ct o

n op

erat

ing

char

acte

ristic

s)

Rol

e

Diag

nosin

g lo

cal

recu

rrenc

e

Dete

cting

liver

met

asta

ses

Dete

ctin

gex

trahe

patic

met

asta

ses

CTAP

=CT

with

arte

rial p

orto

grap

hy

December 1998


All discussed changes in therapeutic management attributable to PET, but themethods for evaluation, details of the work up, or documentation of diseaseseverity among the cases were not described. To suggest that PET improves thepre-operative staging process for selecting more appropriate patients for resectionbased on the existing evidence is ill-advised.

The TA Program did not identify any studies evaluating the efficacy of PET inpost-operative monitoring. There is no consensus on the benefit of routineintensive follow-up after primary treatment, and the timing, frequency, type, andindications for post-operative follow-up using imaging are not standardized(Stotland, 1997). Any evaluation of PET in this role would be in the context ofuncertain benefits of such monitoring.

Appendix II lists two particularly relevant studies for staging colorectal cancerand could serve as models for future PET research. Notable design features arehighlighted. Zerhouni (1996) of the Radiology Diagnostic Oncology Groupconducted a large, multi-site trial to compare the relative accuracies of CT andMRI in staging primary colorectal cancer. Stark (1987) compared CT and MRI todetect liver metastases, an important aspect of staging colorectal cancer patients.Studies of PET that incorporate these features with the comparable level of detailwould provide more robust data on which to more confidently judge the addedvalue of PET in the work up of colorectal cancer.

The TA Program concludes that the prevailing evidence does not support theroutine use of either dedicated or camera-based PET in the management ofcolorectal cancer. Larger, prospective studies of diagnostic accuracy andsubsequent therapeutic efficacy of PET in the work up are needed.Methodologically rigorous studies of diagnostic imaging have been publishedthat may serve as models for guiding design of future PET research. Reviewof the recent evidence confirms the conclusions from the first report.

F. Alzheimer’s Disease

This section briefly summarizes Alzheimer’s disease (AD) and presents updatedepidemiological information and results of a systematic review of the literatureevaluating PET using FDG as a diagnostic test in AD. Appendix 8 of the MDRCtechnology assessment report on PET (Flynn, 1996) provides an expanded discussion ofthe disease, diagnosis, treatment, methodological and ethical considerations, andalternative neuroimaging technologies and other relevant diagnostic tests used in AD.

Unless otherwise noted, epidemiological information is from a consensus statement of theAmerican Association for Geriatric Psychiatry, the Alzheimer’s Association, and theAmerican Geriatrics Society (Small, 1997). AD, a progressive neurodegenerativedisorder, is the most common form of dementia and affects an estimated 4 million peoplein the United States. AD is characterized by steady irreversible decline in cognition,functioning, and behavior with sparing of motor and sensory functions until later stages.The rate of progression is variable, but duration of illness from diagnosis to death isapproximately 10 years.

December 1998


The reported prevalence of AD is approximately 6-8% of all persons 65 years or older. Itdoubles every 5 years after the age of 60 years, so that about 30% of the population olderthan 85 years will have AD. By the next century, an estimated 600,000 veterans withsevere dementia will require long-term institutional care (ORD Impacts, 1997). Thedirect and indirect costs for care of AD patients in the United States approach $100billion annually. The true costs of AD to society is likely much more, as economicassessments frequently underestimate the economic and emotional burden imposed on thecaregivers as well as the patients.

Hendrie (1998) recently summarized the achievements in understanding genetic andnongenetic risk factors associated with AD. Genetic risk factors account for about 2% ofall AD cases. Both causative (mutations on chromosomes 1, 12, 14, and 21) andassociative genes (APOE-4 allele2 on chromosome 19) for AD have been identified. InVA, ORD researchers are: 1) studying genetic and environmental factors that contributeto delayed onset of AD in subjects with chromosome 1 mutations (ORD, 1997), and 2)are following subjects with the APOE-4 allele at higher risk for developing AD to betterdetect and characterize early stages of this disease (Bondi, 1997).

Diagnostic tests that detect the presence of the APOE-4 allele for apolipoprotein E, aserum lipoprotein involved in cholesterol transport, are under investigation, but expertsdiffer on its usefulness. Since the APOE-4 allele is found in many elderly personswithout AD and is not always found in patients with AD, the Working Group of theAmerican Medical Genetics/American Society of Human Genetics concluded thatpredictive testing of APOE-4 for AD should not be done.

The only nongenetic risk factors consistently associated with risk for AD are age andfamily history. Other possible risk factors with a predominately positive associationinclude low education, depression, estrogen-replacement therapy, nonsteroidal anti-inflammatory drugs (NSAIDs). Female gender, head injury, hypothyroidism and, to alesser extent, insulin-dependent diabetes, aluminum exposure and smoking areinconsistently associated with an increased risk for AD. Clinical trials examining the roleof estrogen, NSAIDs, and vitamin E in AD are reportedly underway.

The primary role of diagnostic testing is the differential diagnosis of AD from otherreversible or treatable dementias. A definitive diagnosis is based on a typical clinicalpicture and histopathologic sampling of brain tissue at autopsy. In the absence ofhistologic confirmation, patients with probable AD are often referred to as havingdementia of the Alzheimer’s type (DAT). Two distinct sets of antemortem clinicalcriteria from the following may be used to characterize patients with DAT:

• (NINCDS/ADRDA)--National Institute of Neurologic and Communication Disordersand Stroke and the Alzheimer’s Disease and Related Disorders Association

• (DSM-IIIR or the more recent DSM-IV)--Diagnostic and Statistical Manual forMental Disorders, American Psychiatric Association.

2 In Mendelian genetics, an allele is any alternative form of a gene at a given locus. An allele may express adominant, a recessive, or an intermediate trait.

December 1998


While advanced stage AD is usually easier to diagnose, early stage disease can beproblematic. There is no cure for AD, but psychosocial techniques for behavioralproblems associated with dementia and drug therapies for cognitive impairment havebeen developed, which can improve quality of life. HSR&D researchers found that twoapproaches improve quality of care and reduce costs associated with caring for ADpatients: 1) simulated presence therapy, which uses selected memories through taperecorded conversations to manage problem behaviors in AD patients (Camberg, 1999);and 2) hospice care for managing AD patients with advanced dementia (Volicer, 1994).

New therapy aimed at slowing disease progression is also available. Since it is mosteffective if given at the earliest stages of AD, there is a need for obtaining earlier andmore accurate antemortem diagnoses. Such information would also help patients andtheir families better prepare for future challenges. Functional imaging technologies suchas PET and SPECT have been used to improve diagnostic certainty and to provideinformation on the pathophysiologic basis of AD.

Eight studies of technical efficacy using only dedicated PET scanners met the inclusioncriteria for review. The TA Program was unable to identify published PET studies athigher levels of the Fryback and Thornbury diagnostic efficacy hierarchy. The followingtable summarizes information from these studies. All studies used FDG-PET to studyregional cerebral glucose metabolic rates; Ishii (1997) also measured cerebellar glucosemetabolic rates.

Evidence from recent technical efficacy studies shows a growing interest in the use ofPET to better understand the biological mechanisms of neurodegenerative disease. Theresearch suggests a link between cognitive function, functional imaging data, and theneurobiology of dementia. There is also increasing emphasis in these studies onimproving methods for detecting early stage AD by improving the measurement ofregional brain function. More precisely defined neuroanatomical atlases and methods ofanalysis may help explain the underlying pathophysiology of AD and the differencesbetween diseases and disease progression.

Results from Imamura (1997) and Vander Borght (1997) underscore the limitations inexisting knowledge using PET to diagnose AD. That is, while the temporal and parietalmetabolic patterns often differentiate AD from other causes of dementia, AD also sharesfunctional imaging features with other causes.

December 1998


Table 18: Summary of Recent Technical Efficacy Studies Using FDG PET inAlzheimer’s Disease

Study Objective Findings suggest…Desgranges et al.(1998)

N = 19

To study the neuronal basis for memoryimpairment in AD using Tulving’s hierarchicalmodel of memory systems and PETmeasurement of resting regional cerebralglucose utilization

• Their methodology for mapping neuronal substrates of cognitiveimpairment are valid and useful.

Higuchi et al. (1997)

N = 20

To examine regional cerebral glucosemetabolism using PET in AD patients withdefined genetic risk factors (APOE-4, ACT,and PS-1 genotypes)

• APOE-4 does not adversely affect the AD process or preserve brainmetabolism after clinical onset of AD.

• ACT gene has deleterious effects on cerebral glucose metabolismduring the clinical stages of AD.

• Differences in cerebral regions are influenced by the two genes.• Inheritance pattern of the two alleles may explain divergent patterns

of progression in AD.

Imamura et al. (1997)

N = 38

To study regional cerebral glucosemetabolism in AD vs. dementia with Lewybodies (DLB)

• There are differences in regional glucose hypometabolism consistentwith the pathological and neurochemical differences between DLBand AD.

• FDG-PET may help in the clinical discrimination between DLB andAD.

Ishii et al. (1997)

N = 81

To study regional cerebral and cerebellarglucose metabolic rates in AD

• There is a significant cerebellar glucose metabolic reduction in severeAD with no apparent cerebellar atrophy.

• AD is a global degenerative brain disease in which degeneration iscorrelated with severity.

• Method of analysis using normalization of regional glucose metabolicdata to cerebellar values may be liable to err in severe AD patients.

Pietrini et al. (1997)

N = 16

To study regional glucose metabolism understress using an audiovisual paradigm innondemented adults with trisomy 21 Down’ssyndrome

• There are no differences in metabolism at rest.• In older subjects had significantly lower glucose metabolic rates in the

parietal and temporal cortical areas.• A stress test paradigm can detect metabolic abnormalities in the

preclinical stages of AD.

Stein et al. (1998)

N = 50

Using a template of Brodmann areas derivedfrom whole brain histological section atlas toanalyze glucose metabolic rates in ADpatients

• Vulnerability is greatest in cortical areas that are in closer synapticcontact with limbic areas.

• Integrating statistical techniques of brain imaging intoneuroanatomical atlases and incorporating fine-tuned calibration ofneuroanatomical studies into brain-imaging analyses, may increasecorrelation of findings and a more complete characterization of thepathophysiology of AD.

Vander Borght et al.(1997)

N = 27

To study regional cerebral glucosemetabolism in AD vs. Parkinson’s diseasewith dementia (PDD)

• AD and PDD may share common features in the patterns ofmetabolic alterations and also presence of regional metabolicdifferences in the visual cortex and in the medical temporal cortex.

• These differences may help explain different degrees andcombinations of disease specific underlying pathological andneurochemical processes.

Yamaguchi et al. (1997)

N = 23

To study regional glucose metabolism inhippocampal atrophy in AD

• Morphologic asymmetry of the hippocampus and a metabolicasymmetry of the temporoparieto-occipital were correlated.

• These asymmetries are present in early stage AD.

Summary/Discussion

Recent evidence exploits functional imaging technologies such as PET forpathophysiologic information that may be applied toward earlier preclinicaldiagnoses of AD. Jagust (1996) highlighted the importance and the complexitiesof obtaining earlier and more accurate diagnoses of AD:

• Earlier diagnosis is important for understanding the biological mechanisms ofAD;

December 1998


• Clinically, early diagnosis becomes more critical, as treatments becomeavailable;

• Information from early diagnoses may enable forecasting which elderlypersons who experience memory lapses will develop dementia;

• Normal aging processes can complicate early diagnosis; and• Research should also assess factors key to the production of disease

symptoms.

The best evidence demonstrating the accuracy of FDG PET in diagnosingAlzheimer’s disease is from four published studies reviewed by Flynn (1996).They are listed in the Alzheimer’s disease references (Section XI). Althoughthese studies reported good diagnostic accuracy for PET in AD, the diagnosticutility of PET remains controversial:

• While each set of clinical criteria has different associated sensitivity,specificity, and likelihood ratios, careful application of the clinical criteriadoes appear to identify most cases of treatable dementia.

• Sources of bias attributed to the spectrum and severity of disease, the use ofclinical criteria as the gold standard, and the choice of clinical criteria(NINCDS/ADRDA versus DSM-IIIR or DSM-IV) may have influenceddiagnostic accuracy estimates in these studies.

• Few studies applied PET prospectively to large numbers of patients with aspectrum of dementia and disease severity, which would be necessary todefine the positive predictive value of PET as a diagnostic test, and followedthem until death.

Flynn (1996) reported that a cooperative group of European PET centers isconducting such a study. The study will include patients with NINCDS/ADRDA“possible” AD, the patients in whom there is the greatest uncertainty regardingdiagnosis and for whom a more accurate test would most contribute to posttestcertainty.

Small (1997) suggested that improved diagnostic information to patients and theirfamilies may allow families to better prepare for the challenges ahead and thatearly and accurate diagnosis may prevent the use of costly medical resources.The TA Program was unable to locate any studies of PET that assessed the impactof PET on the costs associated with caring for patients with AD.

Flynn (1996) concluded that existing evidence argues against routine clinicaluse of PET for diagnosing AD until more effective treatments and riskmodification interventions for AD are developed, and until meaningful androbust predictive values are obtained from an ongoing European multicenterPET study.

December 1998


The value of improved diagnostic information to AD patients and theirfamilies should not be dismissed; however, this value should be quantified inthe context of accessibility and accuracy of alternative imaging technologiesand of phenotypically or genetically defined subsets of AD. In the absence ofeffective treatments for AD, an accurate diagnostic test may be neededprimarily in research for epidemiologic studies and evaluations of potentialtherapies.

IX. ONGOING CLINICAL STUDIES AND ON-LINE RESOURCES

Several on-line sources provide useful information about ongoing clinical trials:

• CenterWatch Clinical Trials Listing Service [http://www.centerwatch.com]

• NIH Clinical Research Studies [http://clinicalstudies.info.nih.gov/]

• NCI cancerTrials PDQ database search [http://cancertrials.nci.nih.gov/]

These on-line sources were searched in November 1998 for active clinical trials studying theefficacy of FDG PET. Thirty-eight active protocols using FDG PET were retrieved, of which thefollowing six protocols are assessing diagnostic PET for the conditions reviewed in this report.

Table 19: Active NIH Trials of FDG PET in Selected Cancers and Alzheimer’s Disease

PROTOCOL COMMENTS

NCI-94-C-0151Diagnostic study of PET in patients with stage II-IV or recurrent breast cancer

Single-site

Sponsor- NCI

Start date 1994Active accrual for at least 3 years

MSKCC-97046, NCI-G97-1308Comparison of positron emitter Iodine I124 Iododeoxyuridine with fludeoxyglucose F 18 (F-18-Fluoro-2-Deoxy-(D)-Glucose) as a tracer for glycolysis on scans and in tumor samples in patients with advanced breastcancer

Single site

Sponsor- local funding *

Start date (1997)Active accrual for about 1 year

NCI-97-C-0068Phase II study of Anti-CEA antibody immunoscintigraphy and PET in the localization of recurrent colorectalcarcinoma in patients with rising serum CEA levels in the absence of imageable disease by conventionalmodalities

Single site

Sponsor- NCI

Start date (1997)Active accrual for 3 years

MSKCC-96079, NCI-G97-1334Phase II/III Diagnostic Study of Whole Body PET to measure the response to induction chemotherapy ofpotentially resectable lung and esophageal carcinomas

Single site

Sponsor- local funding *

Start date (1997)Active accrual open

NCI-98-C-0163The use of PET and MRI to assess the effects of anti-neoplastic therapy on tumor associated vasculature

Unknown

Sponsor- NCI

Start date 1998Accrual pending

81-N-0010Study of regional cerebral utilization of glucose in organic dementia and Down syndrome by the Laboratory ofNeurosciences of The National Institute on Aging

Unknown

Sponsor-National Institute of NeurologicalDisorders and Stroke (NINDS)

Start date 1981Active accrual

* Personal communication: Dr. Steven Larson, Memorial Sloan Kettering Cancer Center, New York

Since there is no central repository for locating active clinical trials of PET, these sources maynot provide a complete listing of all multi-site studies evaluating PET as a clinical test.

December 1998


Consequently, individuals actively involved in the use and evaluation of PET were queried fortheir knowledge of other relevant cooperative trials.

• NCI is funding a multi-center trial of FDG PET in staging breast cancer. The primary goalis to assess the accuracy of PET for detecting the presence, absence, and extent of axillarynodal metastases in women with newly diagnosed breast cancer; a secondary endpoint willevaluate PET for detecting internal mammary nodal disease as a prognostic indicator(personal communication: Dr. Barry Siegel, Washington University, St. Louis, Missouri).

• NCI is sponsoring a new cooperative group within the American College of Surgeons calledthe American College of Surgeons Oncology Group (ACoSOG) (NIH, 1998). The ACoSOGwill design and conduct cooperative trials in surgical oncology. The primary goal of theACoSOG is to evaluate surgical approaches for diagnosis and treatment of patients withmalignant solid tumors. Patients with the most common cancers of the breast, lung, andcolo-rectum will be studied initially. Completion of two protocols comparing theincremental value of PET to conventional staging in potentially operable patients with lungcancer and esophageal cancer is imminent (personal communication: Dr. Barry Siegel).

• The Southwest Oncology Group (SWOG) is developing a companion study within a PhaseIII cooperative trial comparing surgery and pre-operative chemotherapy for patients withlung cancer. The companion study will evaluate PET in assessing tumor response tochemotherapy. Both studies will be activated in 1999 (personal communication: SuzanMyers, SWOG).

X. OTHER SYSTEMATIC REVIEWS OF PET

Since 1996 several organizations have conducted assessments to support evidence-basedrecommendations for the use of PET as a diagnostic test (See Appendix V). The majority ofassessments were qualitative systematic reviews of dedicated PET used in neurology to diagnoseand manage patients with medically refractory partial seizures, central nervous system tumors,and cerebrovascular disease. Recent systematic reviews reflect an increasing interest in PET andin other positron imaging modalities to manage patients with non-central nervous systemcancers, emphasizing staging non-small cell lung cancer.

For the indications in this review, the findings of assessments with either full text or abstracts inEnglish in the public domain, or otherwise available to the MDRC, are summarized below:

• There is general agreement that the evidence on FDG-PET for diagnosing, staging ormonitoring treatment of primary cancers outside the lung is not firmly established.

• There is general agreement that the effect of PET on the management of patients withprimary lung cancers is not known.

The Agencia de Evaluación de Tecnologías Sanitarias (AETS) in Spain, the Committee forEvaluation and Diffusion of Innovative Technologies (CEDIT) in France, and the NHSHealth Technology Assessment Programme (NHS HTAP) in the United Kingdomrecommend comparative studies of effectiveness and of the diagnostic contribution of

December 1998


dedicated PET (and, in some cases, coincidence imaging gamma cameras) in patients withlung cancer.

• Assessment findings and recommendations are mixed regarding the use of PET todiagnose and stage non-small cell lung cancer and solitary pulmonary nodules (SPNs).

Two agencies, AETS and the NHS HTAP, used VA review methods and frameworks toupdate and/or expand the first VA PET report (Flynn, 1996). Both reports confirmed VA’soriginal findings that the evidence for the diagnostic efficacy of PET in managing patientswith lung cancer was insufficient. Blue Cross/Blue Shield Association found that FDG-PETimaging meet their quality assessment criteria for staging mediastinal lymph nodes andcharacterizing radiographically indeterminate SPNs, provided the test results could changemedical management (HCFA, 1997).

An ECRI quantitative analysis determined that for both lung cancer indications PET is cost-effective when used to confirm resectability, but that PET is not cost-effective when usedearlier in the diagnostic algorithm. A SPN strategy using CT for initial diagnosis, needlebiopsy to confirm positive results, and PET to confirm negative results attained the greatestlife expectancy (Mitchell, 1998).

There are several possible reasons for the discrepancies across these assessments. Variationsin criteria for including published studies and for judging the quality of the included studies,in analytical methods, in the rationale for the assessment, and in the focus of the report arelikely causes. Often, assessments must be purchased or may require language translation tobe systematically evaluated. For this review, the MDRC considered information availableonly in the public domain in English or with English translation. Proprietary or non-translated reports may have derived different conclusions. Valid comparisons of technologyassessments that address similar topics are critical to health care organizations wishing toestablish policies based on the best available evidence.

Increasingly, agencies are using quantitative analyses, (e.g., decision analyses, meta-analyses, and cost-effectiveness analyses) to quantify the utility of clinical PET. Manyanalyses extrapolate existing diagnostic accuracy estimates to population impact, or poolaccuracy results from multiple studies. It is important to note that the validity of the studiesthat are the source of these estimates is an essential consideration when evaluating therobustness of the results (Petitti, 1994).

• Until recently, agencies considered only dedicated PET scanners, but now are asked toreview other positron imaging modalities.

An expert panel at CEDIT considered coincidence imaging gamma cameras and dedicatedPET in their recommendations. The NHS HTAP report will include evaluations of partialring PET, coincidence imaging gamma cameras, and collimated 511 keV imaging.

PET is a topic for a joint project of the International Network of Agencies for Health TechnologyAssessment (INAHTA), to which the TA Program belongs. The TA Program is coordinating theproject with members from Spain and the Agency for Health Care Policy and Research. Memberagencies are collaborating to synthesize their assessments of clinical PET applications into a

December 1998


single, broadly applicable document. The report will also include a description of the evolutionof PET use in the United States and current indications and coverage policies of PET amongcountries represented by INAHTA members. The report will be available in 1999 on theINAHTA web site at [http://www.inahta.org].

XI. CONCLUSIONS

A. Experience in VA

VHA continues to make a substantial resource commitment to its PET imaging facilities.This commitment has the potential to help support two parts of VHA’s mission: researchand clinical care. The medical community regards PET as an important basic researchtool. A survey of active funded research at VHA PET sites underscores this importance,with the vast majority of basic research activity in neurology and cardiology. VHA ismaximizing its investment in PET by supporting high quality outcomes research andsystematic collection of utilization data.

All VHA PET sites have access to FDG, enabling them to conduct glucose metabolicstudies for various clinical applications. The number of PET oncology studies conductedacross VHA PET facilities from FY 1994 to FY 1998 has nearly quadrupled, likelyreflecting the positive changes in Medicare and private sector reimbursement andchanges in practitioners’ attitudes. Since VHA continues its moratorium on addingdedicated PET centers to its system, many VA medical centers without access todedicated PET scanners are adapting existing dual-headed gamma cameras forcoincidence detection.

B. Systematic reviews

The prevailing evidence does not support the use of either dedicated or gamma camerasmodified for coincidence detection (camera-based PET) as a diagnostic test for theapplications in this review. All studies were subject to considerable bias, which will haveresulted in overestimating accuracy and clinical value. Several studies presentedanecdotal data on the influence of PET on changing diagnostic certainty and treatmentplanning, but the methods for assessing these changes were not described, and thesystematic nature could not be determined.

Caution must be exercised to not apply accuracy estimates from dedicated PET tocamera-based PET systems. Whereas dedicated PET scanners are limited primarily totertiary care institutions, dual-headed gamma camera systems are more widely employed.Technical differences between the two systems and potential differences in the studypopulations represented across different health facilities emphasize the need for large,rigorous studies of diagnostic efficacy to define the clinical role of camera-based PET.

The TA Program identified several methodologically rigorous studies of other diagnosticimaging modalities that could serve as models for designing future PET research(Appendix II). Incorporating aspects from these studies would correct the methodologicshortcomings of the existing literature and strengthen the evidence on which to basefuture patient care decisions.

December 1998


Qualitative systematic reviews produced by other technology assessment agencies, whichused methods similar to the VA PET report, reached similar conclusions. Most agenciesagree that the effect of positron imaging on managing patients with cancer needs furtherstudy. Several cooperative trials and other data collection efforts are ongoing or are beingproposed that may address many unanswered questions regarding the utility of FDG PETin the work up of patients with cancer and Alzheimer’s disease. Clinicians should awaitthe results of these efforts before incorporating PET into routine diagnosticstrategies. Nonetheless, variations across studies in study populations, imagingprotocols, threshold values, and formulae for calculating quantitative uptake values maylimit the generalizability of the findings to other institutions and populations. Review ofrecent evidence confirms the conclusions from the original VA PET assessment(Flynn, 1996).

Information on some of the cooperative trials can be accessed through on-line datasources. Advocates of clinical PET and decision makers interested in its clinicalutility would benefit from an accessible central repository containing information onexisting and proposed rigorously designed cooperative trials of PET. This sourcecould help guide the diffusion of PET into clinical care, as its usefulness and contributionto improved patient outcomes are appropriately evaluated.

December 1998

MTA98-032 MDRC Technology Assessment Program - PET Update - Page R - 1

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Lieberman DA. U.S. Department of Veterans Affairs. Cooperatives Studies Program. (1998).Prospective Evaluation of Risk Factors for Large Colonic Adenomas in Asymptomatic Subjects.[Web Site]. Available: http://www.va.gov/research/files/VA011064.HTM, [April 28, 1999].

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Maublant J. Scintigraphic imaging of breast tumors. Eur J Radiol 1997; 24(1): 2-10.

Mitchell MD, Turkelson C, Doggett D. Cost-effectiveness analysis of PET in lung cancerdiagnosis and staging. Annual Meeting of the International Society for Technology Assessmentin Health Care, Abstracts. Vol. 14; 33, 1998.

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Rifkin MD, Zerhouni EA, Gatsonis CA, Quint LE, Paushter DM, Epstein JI. Comparison ofmagnetic resonance imaging and ultrasonography in staging early prostate cancer. Results of amulti-institutional cooperative trial [see comments]. N Engl J Med 1990; 323(10): 621-626.

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Thornbury JR, Fryback DG, Turski PA, Javid MJ, McDonald JV, Beinlich BR. Disk-causednerve compression in patients with acute low-back pain: diagnosis with MR, CT myelography,and plain CT [published erratum appears in Radiology 1993 Jun;187(3):880] [see comments].Radiology 1993; 186(3): 731-738.

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U.S. Department of Health and Human Services. Health Care Financing Administration. (March8, 1999). Positron Emission Tomography (PET) Scan Coverage Expanded. [Web site].Available: http://www.hcfa.gov/news/pr1999/n990308.htm, [May 3, 1999].

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Vitola JV, Delbeke D, Sandler MP, Campbell MG, Powers TA, Wright Jk. Positron emissiontomography to stage suspected metastatic colorectal carcinoma to the liver. Am J Surg 1996;171(1): 21-26.

Volicer L, Collard A, Hurley A, Bishop C, Kern D, Karon S. Impact of special care unit forpatients with advanced Alzheimer's disease on patients' discomfort and costs [see comments]. JAm Geriatr Soc 1994; 42(6): 597-603.

Wahl RL. Overview of the current status of PET in breast cancer imaging. Quarterly Journal ofNuclear Medicine 1998; 42(1): 1-7.

Webb WR, Gatsonis C, Zerhouni EA, Heelan RT, Glazer GM, Francis IR. CT and MR imagingin staging non-small cell bronchogenic carcinoma: report of the Radiologic Diagnostic OncologyGroup. Radiology 1991; 178(3): 705-713.

Winawer SJ, Fletcher RH, Miller L, Godlee F, Stolar MH, Mulrow CD, et al. Colorectal cancerscreening: clinical guidelines and rationale [see comments] [published errata appear inGastroenterology 1997 Mar;112(3):1060 and 1998 Mar;114(3):625]. Gastroenterology 1997;112(2): 594-642.

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Head and NeckIncluded Studies

Diagnostic Accuracy

December 1998


Lowe VJ, Dunphy FR, Varvares M, Kim H, Wittry M, Dunphy CH, et al. Evaluation ofchemotherapy response in patients with advanced head and neck cancer using [F-18]fluorodeoxyglucose positron emission tomography. Head Neck 1997; 19(8): 666-674.

Myers LL, Wax MK, Nabi H, Simpson GT, Lamonica D. Positron emission tomographyin the evaluation of the N0 neck. Laryngoscope 1998; 108(2): 232-236.

Wong WL, Chevretton EB, McGurk M, Hussain K, Davis J, Beaney R, et al. Aprospective study of PET-FDG imaging for the assessment of head and neck squamouscell carcinoma. Clin Otolaryngol 1997; 22(3): 209-214.

Technical EfficacyBraams JW, Pruim J, Kole AC, Nikkels PG, Vaalburg W, Vermey A, et al. Detection ofunknown primary head and neck tumors by positron emission tomography. Int J OralMaxillofac Surg 1997; 26(2): 112-115.

Kuhn GD, Reisser C, DimitrakopoulouStrauss A, Oberdorfer F, Strauss LG. PET studiesof perfusion and glucose metabolism in patients with untreated head and neck tumours.Onkologie 1997; 20(3): 226-230.

Minn H, Lapela M, Klemi PJ, Grenman R, Leskinen S, Lindholm P, et al. Prediction ofsurvival with fluorine-18-fluorodeoxyglucose and PET in head and neck cancer. JournalOf Nuclear Medicine 1997; 38(12): 1907-1911.

Sakamoto H, Nakai Y, Ohashi Y, Okamura T, Ochi H. Positron emission tomographicimaging of head and neck lesions. Eur Arch Otorhinolaryngol Suppl 1997; 1 pS123-6:

December 1998


Excluded StudiesChanglai SP, Kao CH, Chieng PU. 18F-2-fluoro-2-deoxy-D-glucose positron emissiontomography of head and neck in patients with nasopharyngeal carcinomas. OncologyReports 1997; 4(6): 1331-1334.

McGuirt WF, Greven K, Williams D, 3rd, Keyes JW, Jr., Watson N, Cappellari JO, et al.PET scanning in head and neck oncology: a review. Head Neck 1998; 20(3): 208-215.

Breast CancerIncluded Studies

Diagnostic AccuracyAdler LP, Faulhaber PF, Schnur KC, Al-Kasi NL, Shenk RR. Axillary lymph nodemetastases: Screening with (F-18)2-deoxy-2-fluoro- D-glucose (FDG) PET. Radiology1997; 203(2): 323-327.

Bender H, Kirst J, Palmedo H, Schomburg A, Wagner U, Ruhlmann J, et al. Value of 18fluoro-deoxyglucose positron emission tomography in the staging of recurrent breastcarcinoma. Anticancer Res 1997; 17(3b): 1687-1692.

Crippa F, Agresti R, Seregni E, Greco M, Pascali C, Bogni A, et al. Prospectiveevaluation of fluorine-18-FDG PET in presurgical staging of the axilla in breast cancer. JNucl Med 1998; 39(1): 4-8.

Moon DH, Maddahi J, Silverman DH, Glaspy JA, Phelps ME, Hoh CK. Accuracy ofwhole-body fluorine-18-FDG PET for the detection of recurrent or metastatic breastcarcinoma. J Nucl Med 1998; 39(3): 431-435.

Palmedo H, Bender H, Grunwald F, Mallmann P, Zamora P, Krebs D, et al. Comparisonof fluorine-18 fluorodeoxyglucose positron emission tomography and technetium-99mmethoxyisobutylisonitrile scintimammography in the detection of breast tumours. Eur JNucl Med 1997; 24(9): 1138-1145.

Utech CI, Young CS, Winter PF. Prospective evaluation of fluorine-18fluorodeoxyglucose positron emission tomography in breast cancer for staging of theaxilla related to surgery and immunocytochemistry. Eur J Nucl Med 1996; 23(12): 1588-1593.

Technical EfficacyAvril N, Bense S, Ziegler SI, Dose J, Weber W, Laubenbacher C, et al. Breast imagingwith fluorine-18-FDG PET: quantitative image analysis. J Nucl Med 1997; 38(8): 1186-1191.

Noh DY, Yun IJ, Kim JS, Kang HS, Lee DS, Chung JK, et al. Diagnostic value ofpositron emission tomography for detecting breast cancer. World J Surg 1998; 22(3):223-227; discussion 227-228.Oshida M, Uno K, Suzuki M, Nagashima T, Hashimoto H, Yagata H, et al. Predictingthe prognoses of breast carcinoma patients with positron emission tomography using 2-deoxy-2-fluoro[18F]-D-glucose. Cancer 1998; 82(11): 2227-2234.

December 1998


Torizuka T, Zasadny KR, Recker B, Wahl RL. Untreated primary lung and breastcancers: correlation between F-18 FDG kinetic rate constants and findings of in vitrostudies. Radiology 1998; 207(3): 767-774.

Excluded StudiesCrippa F, Agresti R, Donne VD, Pascali C, Bogni A, Chiesa C, et al. The contribution ofpositron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) in thepreoperative detection of axillary metastases of breast cancer: the experience of the NationalCancer Institute of Milan. Tumori 1997; 83(2): 542-543.

Holle LH, Trampert L, Lung-Kurt S, Villena-Heinsen CE, Puschel W, Schmidt S, et al.Investigations of breast tumors with fluorine-18-fluorodeoxyglucose and SPECT. J NuclMed 1996; 37(4): 615-622.

Katzenellenbogen JA, Welch MJ, Dehdashti F. The development of estrogen and progestinradiopharmaceuticals for imaging breast cancer. Anticancer Res 1997; 17(3b): 1573-1576.

Kole AC, Nieweg OE, Pruim J, Paans AM, Plukker JT, Hoekstra HJ, et al. Standardizeduptake value and quantification of metabolism for breast cancer imaging with FDG and L-[1-11C]tyrosine PET. J Nucl Med 1997; 38(5): 692-696.

Petren-Mallmin M, Andreasson I, Ljunggren O, Ahlstrom H, Bergh J, Antoni G, et al.Skeletal metastases from breast cancer: uptake of 18F-fluoride measured with positronemission tomography in correlation with CT. Skeletal Radiol 1998; 27(2): 72-76.

Lung CancerIncluded Studies

Diagnostic AccuracyBury T, Dowlati A, Paulus P, Corhay JL, Hustinx R, Ghaye B, et al. Whole-body(18)FDG positron emission tomography in the staging of non-small cell lung cancer.European Respiratory Journal 1997; 10(11): 2529-2534.

Erasmus JJ, Patz EF, Jr., McAdams HP, Murray JG, Herndon J, Coleman RE, et al.Evaluation of adrenal masses in patients with bronchogenic carcinoma using 18F-fluorodeoxyglucose positron emission tomography [see comments]. AJR Am JRoentgenol 1997; 168(5): 1357-1360.

Guhlmann A, Storck M, Kotzerke J, Moog F, Sunder-Plassmann L, Reske SN. Lymphnode staging in non-small cell lung cancer: evaluation by [18F] FDG positron emissiontomography (PET). Thorax 1997; 52(5): 438-441.Sasaki M, Ichiya Y, Kuwabara Y, Akashi Y, Yoshida T, Fukumura T, et al. Theusefulness of FDG positron emission tomography for the detection of mediastinal lymphnode metastases in patients with non-small cell lung cancer: a comparative study with X-ray computed tomography. Eur J Nucl Med 1996; 23(7): 741-747.

Vansteenkiste JF, Stroobants SG, De Leyn PR, Dupont PJ, Verschakelen JA, NackaertsKL, et al. Mediastinal lymph node staging with FDG-PET scan in patients with

December 1998


potentially operable non-small cell lung cancer: a prospective analysis of 50 cases.Leuven Lung Cancer Group. Chest 1997; 112(6): 1480-1486.

Technical EfficacyBury T, Paulus P, Dowlati A, Corhay JL, Rigo P, Radermecker MF. Evaluation ofpleural diseases with FDG-PET imaging: Preliminary report. Thorax 1997; 52(2): 187-189.

Ferlin G, Rubello D, Chierichetti F, Zanco P, Bergamin R, Trento P, et al. The role offluorine-18-deoxyglucose (FDG) positron emission tomography (PET) whole body scan(WBS) in the staging and follow-up of cancer patients: Our first experience. Tumori1997; 83(3): 679-684.

Higashi K, Nishikawa T, Seki H, Oguchi M, Nambu Y, Ueda Y, et al. Comparison offluorine-18-FDG PET and thallium-201 SPECT in evaluation of lung cancer. Journal OfNuclear Medicine 1998; 39(1): 9-15.

Kim BT, Kim Y, Lee KS, Yoon SB, Cheon EM, Kwon OJ, et al. Localized form ofbronchioloalveolar carcinoma: FDG PET findings. AJR Am J Roentgenol 1998; 170(4):935-939.

Nettelbladt OS, Sundin AE, Valind SO, Gustafsson GR, Lamberg K, Langstrom B, et al.Combined fluorine-18-FDG and carbon-11-methionine PET for diagnosis of tumors inlung and mediastinum. J Nucl Med 1998; 39(4): 640-647.

Torizuka T, Zasadny KR, Recker B, Wahl RL. Untreated primary lung and breastcancers: correlation between F-18 FDG kinetic rate constants and findings of in vitrostudies. Radiology 1998; 207(3): 767-774.

Wang H, Maurea S, Mainolfi C, Fiore F, Gravina A, Panico MR, et al. Tc-99m MIBIscintigraphy in patients with lung cancer. Comparison with CT and fluorine-18 FDG PETimaging. Clin Nucl Med 1997; 22(4): 243-249.

Excluded StudiesErasmus JJ, McAdams HP, Patz EF, Jr., Coleman RE, Ahuja V, Goodman PC. Evaluation ofprimary pulmonary carcinoid tumors using FDG PET. AJR Am J Roentgenol 1998; 170(5):1369-1373.

Erdi YE, Mawlawi O, Larson SM, Imbriaco M, Yeung H, Finn R, et al. Segmentation oflung lesion volume by adaptive positron emission tomography image thresholding. Cancer1997; 80(12 Suppl): 2505-2509.

SPNIncluded Studies

Diagnostic AccuracyDewan NA, Shehan CJ, Reeb SD, Gobar LS, Scott WJ, Ryschon K. Likelihood ofmalignancy in a solitary pulmonary nodule: comparison of Bayesian analysis and resultsof FDG-PET scan. Chest 1997; 112(2): 416-422.

December 1998


Lowe VJ, Fletcher JW, Gobar L, Lawson M, Kirchner P, Valk P, et al. Prospectiveinvestigation of positron emission tomography in lung nodules. J Clin Oncol 1998;16(3): 1075-1084.

Excluded StudiesLowe VJ, Duhaylongsod FG, Patz EF, Delong DM, Hoffman JM, Wolfe WG, et al.Pulmonary abnormalities and PET data analysis: a retrospective study [see comments].Radiology 1997; 202(2): 435-439.

Colorectal CancerIncluded Studies

Diagnostic AccuracyDelbeke D, Vitola JV, Sandler MP, Arildsen RC, Powers TA, Wright JK, Jr., et al.Staging recurrent metastatic colorectal carcinoma with PET. J Nucl Med 1997; 38(8):1196-1201.

Flanagan FL, Dehdashti F, Ogunbiyi OA, Kodner IJ, Siegel BA. Utility of FDG-PET forinvestigating unexplained plasma CEA elevation in patients with colorectal cancer [seecomments]. Ann Surg 1998; 227(3): 319-323.

Ogunbiyi OA, Flanagan FL, Dehdashti F, Siegel BA, Trask DD, Birnbaum EH, et al.Detection of recurrent and metastatic colorectal cancer: Comparison of position emissiontomography and computed tomography. Annals of Surgical Oncology 1997; 4(8): 613-620.

Technical EfficacyAbdel-Nabi H, Doerr RJ, Lamonica DM, Cronin VR, Galantowicz PJ, Carbone GM, etal. Staging of primary colorectal carcinomas with fluorine-18 fluorodeoxyglucosewhole-body PET: correlation with histopathologic and CT findings. Radiology 1998;206(3): 755-760.

Ruhlmann J, Schomburg A, Bender H, Oehr P, Robertz-Vaupel GM, Vaupel H, et al.Fluorodeoxyglucose whole-body positron emission tomography in colorectal cancerpatients studied in routine daily practice. Dis Colon Rectum 1997; 40(10): 1195-1204.

Alzheimer’s DiseaseIncluded Studies

Diagnostic Accuracy (reviewed in 1996 report)Burdette JH, Minoshima S, Vander Borght T, Tran DD, Kuhl DE. Alzheimer disease:improved visual interpretation of PET images by using three-dimensional stereotaxicsurface projections. Radiology 1996; 198(3): 837-843.

Herholz K, Perani D, Salmon E, Franck G, Fazio F, Heiss WD, et al. Comparability ofFDG PET studies in probable Alzheimer's disease. J Nucl Med 1993; 34(9): 1460-1466.

December 1998


Kippenhan JS, Barker WW, Nagel J, Grady C, Duara R. Neural-network classification ofnormal and Alzheimer's disease subjects using high-resolution and low-resolution PETcameras [see comments]. J Nucl Med 1994; 35(1): 7-15.

Salmon E, Sadzot B, Maquet P, Degueldre C, Lemaire C, Rigo P, et al. Differentialdiagnosis of Alzheimer's disease with PET. J Nucl Med 1994; 35(3): 391-398.

Technical EfficacyDesgranges B, Baron JC, de la Sayette V, Petit-Taboue MC, Benali K, Landeau B, et al.The neural substrates of memory systems impairment in Alzheimer's disease: A PETstudy of resting brain glucose utilization. Brain 1998; 121(Pt 4): 611-631.

Higuchi M, Arai H, Nakagawa T, Higuchi S, Muramatsu T, Matsushita S, et al. Regionalcerebral glucose utilization is modulated by the dosage of apolipoprotein E type 4 alleleand alpha1-antichymotrypsin type A allele in Alzheimer's disease. Neuroreport 1997;8(12): 2639-2643.

Imamura T, Ishii K, Sasaki M, Kitagaki H, Yamaji S, Hirono N, et al. Regional cerebralglucose metabolism in dementia with Lewy bodies and Alzheimer's disease: Acomparative study using positron emission tomography. Neuroscience Letters 1997;235(1-2): 49-52.

Ishii K, Sasaki M, Kitagaki H, Yamaji S, Sakamoto S, Matsuda K, et al. Reduction ofcerebellar glucose metabolism in advanced Alzheimer's disease. J Nucl Med 1997; 38(6):925-928.

Pietrini P, Dani A, Furey ML, Alexander GE, Freo U, Grady CL, et al. Low glucosemetabolism during brain stimulation in older Down's syndrome subjects at risk forAlzheimer's disease prior to dementia. Am J Psychiatry 1997; 154(8): 1063-1069.

Stein DJ, Buchsbaum MS, Hof PR, Siegel BV, Jr., Shihabuddin L. Greater metabolicrate decreases in hippocampal formation and proisocortex than in neocortex inAlzheimer's disease. Neuropsychobiology 1998; 37(1): 10-19.

Vander Borght T, Minoshima S, Giordani B, Foster NL, Frey KA, Berent S, et al.Cerebral metabolic differences in Parkinson's and Alzheimer's diseases matched fordementia severity. J Nucl Med 1997; 38(5): 797-802.

Yamaguchi S, Meguro K, Itoh M, Hayasaka C, Shimada M, Yamazaki H, et al.Decreased cortical glucose metabolism correlates with hippocampal atrophy inAlzheimer's disease as shown by MRI and PET. J Neurol Neurosurg Psychiatry 1997;62(6): 596-600.

Excluded StudiesAlbin RL, Minoshima S, D'Amato CJ, Frey KA, Kuhl DA, Sima AA. Fluoro-deoxyglucosepositron emission tomography in diffuse Lewy body disease. Neurology 1996; 47(2): 462-466.

December 1998


Bergman H, Chertkow H, Wolfson C, Stern J, Rush C, Whitehead V, et al. HM-PAO(CERETEC) SPECT brain scanning in the diagnosis of Alzheimer's disease. Journal Of theAmerican Geriatrics Society 1997; 45(1): 15-20.

de Leon MJ, McRae T, Rusinek H, Convit A, De Santi S, Tarshish C, et al. Cortisol reduceshippocampal glucose metabolism in normal elderly, but not in Alzheimer's disease. J ClinEndocrinol Metab 1997; 82(10): 3251-3259.

Kondoh Y, Nagata K, Sasaki H, Hatazawa J. Dynamic FDG-PET study in probableAlzheimer's disease. Ann N Y Acad Sci 1997; 826: 406-409.

Marcus DL, Freedman ML. Decreased brain glucose metabolism in microvessels frompatients with Alzheimer's disease. Ann N Y Acad Sci 1997; 826: 248-253.

Mega MS, Chen SS, Thompson PM, Woods RP, Karaca TJ, Tiwari A, et al. Mappinghistology to metabolism: coregistration of stained whole-brain sections to premortem PET inAlzheimer's disease. Neuroimage 1997; 5(2): 147-153.

Meguro K, Yamaguchi S, Itoh M, Fujiwara T, Yamadori A. Striatal dopamine metabolismcorrelated with frontotemporal glucose utilization in Alzheimer's disease: a double-tracerPET study. Neurology 1997; 49(4): 941-945.

Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, Kuhl DE. Metabolic reduction inthe posterior cingulate cortex in very early Alzheimer's disease. Ann Neurol 1997; 42(1): 85-94.

December 1998

MTA98-032 MDRC Technology Assessment Program - PET Update - Page E - 1

XIII. EPILOGUE

On January 28, 1999 the TA Program conducted a final update of the literature by searching theliterature published from July 6, 1998 through December 31, 1998 using the same search andappraisal strategies described in Appendix 1. Titles and abstracts of 346 citations were screened.Forty-one were determined to be relevant, and their full text articles were reviewed for potentialinclusion in the review.

Thirty articles from the database searches and from end references of initially retrieved articlesmet inclusion criteria for review. Each included study was classified according to clinicalcondition and assigned to a diagnostic efficacy level as follows:

Efficacy level*H

ead

& N

eck

Brea

st

Lung

sta

ging

SPN

Col

orec

tal

Alzh

eim

er’s

Technical 3 1 6 0 0 7*Diagnostic accuracy 5 1 5** 1 0 0Diagnostic thinking †TherapeuticPatient outcome 1Societal*includes 6 overlapping studies from same institution**includes 3 overlapping studies from same institution (Vansteenkiste, 1998a,b,c)†diagnostic thinking data and diagnostic accuracy data provided from one study (Vansteenkiste, 1998a)

All of the studies represented are single-site case series. All studies used dedicated PET systems.PET was usually added in the work up to complement anatomic imaging data, and most wereretrospective analyses.

As in the main report, recent studies of FDG PET in Alzheimer’s disease explore therelationships between regional glucose metabolism and cognitive function and are classified astechnical efficacy studies. Several studies of diagnostic PET in oncology met inclusion forreview and could be classified at higher levels of diagnostic efficacy. Five studies in lung cancerstaging, three from the same institution (Vansteenkiste, 1998a; 1998b; 1998c) were continuationsof studies reviewed in the main report with overlapping study populations (Bury, 1998; Weder,1998)

The diagnostic accuracy studies were further appraised for study quality and content. None of thestudies met strict evidence-based medicine criteria for evaluations of diagnostic tests, as theextent of blinding was either not clearly reported or was incomplete. However, two met most ofthe criteria and had reasonably well reported and designed studies, despite their small sizes(Smith, 1998; Präuer, 1998). All studies used patients with no metastases or with benigndiseases as internal controls, and all reported using an objective gold standard. Expanded criteriafor methodologic quality of diagnostic accuracy studies used by the American College ofPhysicians yielded the following quality scores:

December 1998


Table 20: Methodologic Quality of Diagnostic Accuracy Studies of FDG PET inSelected Cancers

MethodologicQuality Grade*

Hea

d &

Nec

k

Brea

st

Lung

sta

ging

SPN

Col

orec

tal

ABC 1 3 1D 5 2

Studies received overall quality scores of “D” if the presence of referral bias and methodologicbiases related to the association between test interpretation and gold standard diagnosis were notminimized in the study. Studies received a “C” because of small study sizes, incompletereporting of critical study design elements, and/or a study design that minimized the effect ofmethodologic biases. Several asserted the potential for PET to directly affect patientmanagement, but this was not systematically assessed in any study.

Two studies were classified either as diagnostic thinking efficacy (Vansteenkiste, 1998a) orpatient outcome efficacy (Gambhir, 1998). Expanding on their study reviewed in the mainreport, Vansteenkiste (1998a) used ROC analysis with PET to calculate optimal accuracy andlikelihood ratios (LR) for estimating the probability of nodal metastases in 690 lymph nodestations in 68 patients with non-small cell lung cancer. For their study population, a cut-off SUVof 4.40 provided optimal accuracy. Based on these data, the authors suggested that positive LRsfor SUVs <3.5 or >4.5 offered high diagnostic value and recommended the following:

• The high negative predictive value of mediastinal CT+PET is sufficient to exclude N2/N3disease, to exclude malignancy in individual node stations and, therefore, to omit invasivemediastinal staging.

• Despite the high positive predictive value of CT+PET, mediastinoscopy is still advised inpatients with a positive mediastinal PET to ensure that no patient with N0 or N1 disease isdenied curative resection based on a false positive PET.

LRs can vary with severity of disease in the case mix and positivity criteria (different thresholdvalues) used for interpretation of both imaging tests. There were few benign conditions that maycontribute to false positive diagnoses on CT and PET, and only four patients had confirmed N3disease. The authors calculated positive LRs for both CT and quantitative PET but did not reportthe probability of nodal metastases before CT. In the absence of knowing the pre-test probabilityof malignancy, LRs are inconclusive for assessing the impact of the test on diagnosis ortreatment planning, and these findings should be interpreted cautiously.

Gambhir (1998) conducted a cost-effectiveness analysis to compare various strategies fordiagnosing and managing SPNs. Expanding on a decision analysis by Cummings (1986), theauthors incorporated PET into a CT-based strategy for patients with noncalcified solitarypulmonary nodules < 3cm in diameter. They concluded that a CT-plus-PET strategy was themost cost-effective over a wide range of pre-CT probabilities of malignancy (0.12 to 0.69), andoffered cost savings over the CT-alone strategy ranging from $91 to $2,200 per patient.

December 1998


The assumptions upon which the analysis is based may affect the stability of the conclusions.PET sensitivity and specificity estimates were based on data from one abstract and biasedestimates from three peer-reviewed studies, which were reviewed in the first VA PET report(Flynn, 1996). The model did not account for the possibility of an indeterminate PET scan.Payment and charge data used in the analysis may not adequately reflect true costs or besufficiently comprehensive to reflect the true work-up of these patients.

The MDRC agrees with the authors’ statement that “this analysis is not a substitute for clinicaltrials, but a guide to the design of clinical trials.” The MDRC does not agree with the authors’statement that “there is significant savings when using a PET-based strategy. This warrants amore widespread dissemination of the technology.” Given the preliminary nature of theassumptions, a more widespread dissemination of the technology based on the results of thiscost-effectiveness analysis would be premature.

Conclusion

Recent studies from 1998 do not provide conclusive evidence to support the use of PET in thework up of patients with the cancers assessed in this report. Prospective, rigorously designedstudies with a sufficient spectrum of patients are needed to assess the incremental value of PETin these patients. The impact of PET results on treatment planning has been alleged, but furtherresearch designed to assess impact on treatment management and associated costs is needed. Thefindings from recent 1998 studies confirm the conclusions and recommendations in the mainreport.

December 1998


References

BackgroundCummings SR, Lillington GA, Richard RJ. Managing solitary pulmonary nodules. The choiceof strategy is a "close call." Am Rev Respir Dis 1986; 134(3): 453-460.

Laupacis A, Wells G, Richardson WS, Tugwell P. Users' guides to the medical literature. V.How to use an article about prognosis. Evidence-Based Medicine Working Group. JAMA 1994;272(3): 234-237.

Phelps CE. Good technologies gone bad: how and why the cost-effectiveness of a medicalintervention changes for different populations. Med Decis Making 1997; 17(1): 107-117.

Head and NeckIncluded Studies

Diagnostic AccuracyAdams S, Baum RP, Stuckensen T, Bitter K, Hor G. Prospective comparison of 18F-FDG PET with conventional imaging modalities (CT, MRI, US) in lymph node stagingof head and neck cancer. Eur J Nucl Med 1998; 25(9): 1255-1260.

Fischbein NJ, Aassar OS, Caputo GR, Kaplan MJ, Singer MI, Price DC, et al. Clinicalutility of positron emission tomography with F-18-fluorodeoxyglucose in detectingresidual/recurrent squamous cell carcinoma of the head and neck. American Journal OfNeuroradiology 1998; 19(7): 1189-1196.

Kao CH, ChangLai SP, Chieng PU, Yen RF, Yen TC. Detection of recurrent orpersistent nasopharyngeal carcinomas after radiotherapy with 18-fluoro-2-deoxyglucosepositron emission tomography and comparison with computed tomography. J Clin Oncol1998; 16(11): 3550-3555.

Manolidis S, Donald PJ, Volk P, Pounds TR. The use of positron emission tomographyscanning in occult and recurrent head and neck cancer. Acta Otolaryngol Suppl 1998;534(11): 1-11.

Paulus P, Sambon A, Vivegnis D, Hustinx R, Moreau P, Collignon J, et al. 18FDG-PETfor the assessment of primary head and neck tumors: clinical, computed tomography, andhistopathological correlation in 38 patients. Laryngoscope 1998; 108(10): 1578-1583.

Technical EfficacyCollins BT, Gardner LJ, Verma AK, Lowe VJ, Dunphy FR, Boyd JH. Correlation of fineneedle aspiration biopsy and fluoride-18 fluorodeoxyglucose positron emissiontomography in the assessment of locally recurrent and metastatic head and neckneoplasia. Acta Cytol 1998; 42(6): 1325-1329.

Kole AC, Nieweg OE, Pruim J, Hoekstra HJ, Koops HS, Roodenburg JL, et al. Detectionof unknown occult primary tumors using positron emission tomography. Cancer 1998;82(6): 1160-1166.

December 1998


Uematsu H, Sadato N, Yonekura Y, Tsuchida T, Nakamura S, Sugimoto K, et al.Coregistration of FDG PET and MRI of the head and neck using normal distribution ofFDG. J Nucl Med 1998; 39(12): 2121-2127.

Excluded StudiesDavis JP, Maisey MN, Chevretton EB. Positron emission tomography--a useful imagingtechnique for otolaryngology, head and neck surgery? [editorial]. J Laryngol Otol 1998;112(2): 125-127.

Breast CancerIncluded Studies

Diagnostic AccuracySmith IC, Ogston KN, Whitford P, Smith FW, Sharp P, Norton M, et al. Staging of theaxilla in breast cancer: accurate in vivo assessment using positron emission tomographywith 2-(fluorine-18)-fluoro-2-deoxy-D-glucose. Ann Surg 1998; 228(2): 220-227.

Technical EfficacyCook GJ, Houston S, Rubens R, Maisey MN, Fogelman I. Detection of bone metastasesin breast cancer by 18FDG PET: differing metabolic activity in osteoblastic andosteolytic lesions. J Clin Oncol 1998; 16(10): 3375-3379.

Excluded StudiesDehdashti F, Flanagan FL, Mortimer JE, Katzenellenbogen JA, Welch MJ, Siegel BA.Positron emission tomographic assessment of "metabolic flare" to predict response ofmetastatic breast cancer to antiestrogen therapy. Eur J Nucl Med 1999; 26(1): 51-56.

Flanagan FL, Dehdashti F, Siegel BA. PET in breast cancer. Seminars in Nuclear Medicine1998.

Greco M, Agresti R, Giovanazzi R. Impact of the diagnostic methods on the therapeuticstrategies. Q J Nucl Med 1998; 42(1): 66-80.

Paganelli G, De Cicco C, Cremonesi M, Prisco G, Calza P, Luini A, et al. Optimizedsentinel node scintigraphy in breast cancer. Q J Nucl Med 1998; 42(1): 49-53.

Lung CancerIncluded Studies

Diagnostic AccuracyBury T, Barreto A, Daenen F, Barthelemy N, Ghaye B, Rigo P. Fluorine-18deoxyglucose positron emission tomography for the detection of bone metastases inpatients with non-small cell lung cancer. Eur J Nucl Med 1998; 25(9): 1244-1247.

Vansteenkiste JF, Stroobants SG, De Leyn PR, Dupont PJ, Verbeken EK, Potential useof FDG-PET scan after induction chemotherapy in surgically staged IIIa-N-2 non-small-cell lung cancer: A prospective pilot study. Annals Of Oncology 1998; 9(11): 1193-1198.

Vansteenkiste JF, Stroobants SG, Dupont PJ, De Leyn PR, De Wever WF, Verbeken EK,et al. FDG-PET scan in potentially operable non-small cell lung cancer: do

December 1998


anatometabolic PET-CT fusion images improve the localisation of regional lymph nodemetastases? The Leuven Lung Cancer Group. Eur J Nucl Med 1998; 25(11): 1495-1501.

Vansteenkiste JF, Stroobants SG, De Leyn PR, Dupont PJ, Bogaert J, Maes A, et al.Lymph node staging in non-small-cell lung cancer with FDG-PET scan: a prospectivestudy on 690 lymph node stations from 68 patients. J Clin Oncol 1998; 16(6): 2142-2149.

Weder W, Schmid RA, Bruchhaus H, Hillinger S, von Schulthess GK, Steinert HC.Detection of extrathoracic metastases by positron emission tomography in lung cancer.Ann Thorac Surg 1998; 66(3): 886-892; discussion 892-883.

Technical EfficacyAhuja V, Coleman RE, Herndon J, Patz EF, Jr. The prognostic significance offluorodeoxyglucose positron emission tomography imaging for patients with non-smallcell lung carcinoma. Cancer 1998; 83(5): 918-924.

Gupta N, Gill H, Graeber G, Bishop H, Hurst J, Stephens T. Dynamic positron emissiontomography with F-18 fluorodeoxyglucose imaging in differentiation of benign frommalignant lung/mediastinal lesions. Chest 1998; 114(4): 1105-1111.

Higashi K, Ueda Y, Seki H, Yuasa K, Oguchi M, Noguchi T, et al. Fluorine-18-FDGPET imaging is negative in bronchioloalveolar lung carcinoma. J Nucl Med 1998; 39(6):1016-1020.

Imran MB, Kubota K, Yamada S, Fukuda H, Yamada K, Fujiwara T, et al. Lesion-to-background ratio in nonattenuation-corrected whole-body FDG PET images. J Nucl Med1998; 39(7): 1219-1223.

Kiffer JD, Berlangieri SU, Scott AM, Quong G, Feigen M, Schumer W, et al. Thecontribution of 18F-fluoro-2-deoxy-glucose positron emission tomographic imaging toradiotherapy planning in lung cancer. Lung Cancer 1998; 19(3): 167-177.

Kutlu CA, Pastorino U, Maisey M, Goldstraw P. Selective use of PET scan in thepreoperative staging of NSCLC. Lung Cancer 1998; 21(3): 177-184.

Excluded StudiesErasmus JJ, McAdams HP, Patz EF, Jr., Coleman RE, Ahuja V, Goodman PC. Evaluation ofprimary pulmonary carcinoid tumors using FDG PET. AJR Am J Roentgenol 1998; 170(5):1369-1373.

Laymon CM, Turkington TG, Coleman RE. Attenuation effects in gamma-cameracoincidence imaging. IEEE Transactions on Nuclear Science 1998; 45(6): 3115-3121.

Lowe VJ, Naunheim KS. Positron emission tomography in lung cancer. Ann Thorac Surg1998; 65(6): 1821-1829.

December 1998


SPNIncluded Studies

Diagnostic AccuracyPrauer HW, Weber WA, Romer W, Treumann T, Ziegler SI, Schwaiger M. Controlledprospective study of positron emission tomography using the glucose analogue [18f]fluorodeoxyglucose in the evaluation of pulmonary nodules. Br J Surg 1998; 85(11):1506-1511.

Patient Outcome EfficacyGambhir SS, Shepherd JE, Shah BD, Hart E, Hoh CK, Valk PE, et al. Analyticaldecision model for the cost-effective management of solitary pulmonary nodules. J ClinOncol 1998; 16(6): 2113-2125.

Colorectal CancerExcluded Studies

Miraldi F, Vesselle H, Faulhaber PF, Adler LP, Leisure GP. Elimination of artifactualaccumulation of FDG in PET imaging of colorectal cancer. Clin Nucl Med 1998; 23(1):3-7.

Alzheimer’s DiseaseIncluded Studies

Technical EfficacyHirono N, Mori E, Ishii K, Imamura T, Shimomura T, Tanimukai S, et al. Regionalmetabolism: associations with dyscalculia in Alzheimer's disease. J Neurol NeurosurgPsychiatry 1998; 65(6): 913-916.

Hirono N, Mori E, Ishii K, Ikejiri Y, Imamura T, Shimomura T, et al. Hypofunction inthe posterior cingulate gyrus correlates with disorientation for time and place inAlzheimer's disease. J Neurol Neurosurg Psychiatry 1998; 64(4): 552-554.

Hirono N, Mori E, Ishii K, Ikejiri Y, Imamura T, Shimomura T, et al. Regionalhypometabolism related to language disturbance in Alzheimer's disease. Dement GeriatrCogn Disord 1998; 9(2): 68-73.

Hirono N, Mori E, Ishii K, Ikejiri Y, Imamura T, Shimomura T, et al. Frontal lobehypometabolism and depression in Alzheimer's disease. Neurology 1998; 50(2): 380-383.

Ibanez V, Pietrini P, Alexander GE, Furey ML, Teichberg D, Rajapakse JC, et al.Regional glucose metabolic abnormalities are not the result of atrophy in Alzheimer'sdisease. Neurology 1998; 50(6): 1585-1593.

Ishii K, Sasaki M, Yamaji S, Sakamoto S, Kitagaki H, Mori E. Relatively preservedhippocampal glucose metabolism in mild Alzheimer's disease. Dement Geriatr CognDisord 1998; 9(6): 317-322.

December 1998


Ishii K, Sakamoto S, Sasaki M, Kitagaki H, Yamaji S, Hashimoto M, et al. Cerebralglucose metabolism in patients with frontotemporal dementia. J Nucl Med 1998; 39(11):1875-1878.

Excluded StudiesAlavi A, Clark C, Fazekas F. Cerebral ischemia and Alzheimer's disease: critical role of PETand implications for therapeutic intervention. J Nucl Med 1998; 39(8): 1363-1365.

Frey KA, Minoshima S, Kuhl DE. Neurochemical imaging of Alzheimer's disease and otherdegenerative dementias. Q J Nucl Med 1998; 42(3): 166-178.

Small GW, Leiter F. Neuroimaging for diagnosis of dementia. J Clin Psychiatry 1998;59(11): 4-7.

December 1998

MTA98-032 MDRC Technology Assessment Program - PET Update - Page A1-1

XIV. APPENDIX 1

Methods for the Systematic Review

The MDRC performed a systematic review of the published literature to address the diagnosticefficacy of PET in selected cancer applications and Alzheimer’s disease. A systematic reviewdiffers from a traditional narrative literature review in that it uses a rigorous scientific approachto limit bias and to improve the accuracy of conclusions based on the available data (Guyatt,1995). A systematic review addresses a focused clinical question, uses appropriate and explicitcriteria to select studies for inclusion, conducts a comprehensive search, and appraises thevalidity of the individual studies in a reproducible manner.

Consistent with established methods for conducting a systematic review, the MDRC developedcriteria to select studies for inclusion, conducted a comprehensive search, and appraised thevalidity of the individual studies in a reproducible fashion using the analytic frameworkspresented below.

Search Strategy

An update of the literature was carried out by thoroughly searching the literature published fromSeptember 1996 through July 6, 1998. MEDLINE, HealthSTAR, EMBASE, CurrentContents, and BIOSIS were searched using a range of descriptors: tomography, emissioncomputed; positron emission tomography; gamma camera; PET; and other synonyms. Thesewere combined with the descriptors for Alzheimer’s, colorectal neoplasms, breast neoplasms,head and neck neoplasms, and lung neoplasms. Over 400 citations were retrieved.

Inclusion Criteria

All published studies included in this report met the following inclusion criteria:

• English language articles reporting primary data and published in a peer reviewjournal (not abstracts);

• studies > 12 human subjects (not animal studies) with the disease of interest;• studies using positron emission transverse tomography or positron emission

coincidence imaging;• studies using the radiopharmaceutical 2-[18F]fluoro-2-D-glucose (FDG);• study not duplicated or superseded by later study with the same purpose from the

same institution; and• study design and methods clearly described (i.e. sufficient information to judge

comparability of case and control groups, details of imaging protocol, whether visualor quantitative analysis of PET data used, or type of PET quantitative data analysisused).

Methodologic standards for studies

December 1998


The purpose of appraising the literature using clearly defined methodologic criteria is to ensurethat studies are evaluated in a consistent, reproducible manner, and that studies included in thereport conform to established scientific standards. Studies reviewed for possible inclusion in thisreport were classified according to the strength of the evidence they provided, and the strongestavailable evidence for each application was summarized. The strength of a study is based on theoverall research design and on the quality of the implementation and analysis. The methodologicstandards and the types of studies to which they were applied are summarized below. Thestandards are also discussed in the MDRC report Assessing Diagnostic Technologies (Flynn,1996).

1. Assign to level of diagnostic efficacy hierarchy

Accurate estimation of the characteristics of a diagnostic test is one of the early steps inthe assessment of that test. However, a complete assessment requires further research.

Fryback and Thornbury (1991) note that the localized view of the goal of diagnosticradiology would be that it provides the best images and the most accurate diagnosespossible. A more global view recognizes diagnostic radiology as part of a larger systemof medical care whose goal is to treat patients effectively and efficiently. Viewed in thislarger context, even high-quality images may not contribute to improved care in someinstances, and images of lesser quality may be of great value in others. The point of thesystematic view may be to examine the ultimate value or benefit that is derived from anyparticular diagnostic examination.

Fryback and Thornbury (1991; 1992) present the most recent manifestation of anevolving hierarchical model for assessing the efficacy of diagnostic imaging procedures.Their model, with a list of the types of measures that appear in the literature at each levelin the hierarchy, is presented in the next table. The table progresses from the micro, orlocal level, at which the concern is the physical imaging process itself, to the societalefficacy level. The model stipulates that for a procedure to be efficacious at a higherlevel in the hierarchy it must be efficacious at the lower levels, but the reverse is not true;this asymmetry is often lost in research reports at Levels 1 and 2. Using this model, it ispossible to follow the development of a diagnostic technology, and to align currentresearch efforts with a particular level of development.

December 1998


Com

men

ts

• Ph

ysica

l par

amet

ers

desc

ribin

g te

chni

cal im

agin

g qu

ality

• Jo

int fu

nctio

n of

imag

es a

nd o

bser

ver

• Al

so a

func

tion

of c

linici

an w

ho re

ques

ts d

iagn

ostic

pro

cedu

re, s

ince

sel

ectio

nco

ntro

ls sp

ecific

ity o

f tes

t in

clini

cal p

ract

ice a

nd s

ensit

ivity

to th

e ex

tent

that

itva

ries

with

the

spec

trum

of t

he d

iseas

e

• In

ducin

g ch

ange

in c

linici

ans’

diag

nost

ic th

inkin

g is

a ne

cess

ary

prer

equi

site

toim

pact

on p

atien

ts.•

Clin

ician

s m

ay v

alue

resu

lts w

hich

reas

sure

them

, but

whi

ch d

o no

t cha

nge

treat

men

t dec

ision

s.•

Empi

rical

met

hods

to m

easu

re c

hang

e in

pre

test

dia

gnos

tic p

roba

biliti

es a

ssum

edby

clin

ician

s ar

e pr

obab

ly be

st fo

r det

erm

inin

g th

e ab

senc

e of

dia

gnos

tic th

inkin

gef

ficac

y, ra

ther

than

est

imat

ing

the

mag

nitu

de o

f cha

nge

in d

iagn

ostic

thin

king

due

to im

agin

g in

form

atio

n.•

Imag

ing

exam

inat

ion

resu

lt m

ay in

fluen

ce c

linici

an’s

diag

nost

ic th

inkin

g, b

ut h

as n

oim

pact

on p

atien

t tre

atm

ent.

• In

situ

atio

ns w

here

RCT

s of

dec

ision

mak

ing

with

and

with

out t

he im

agin

gin

form

atio

n ca

nnot

be

perfo

rmed

eth

ically

or b

ecau

se o

f the

mom

entu

m fo

r usin

g a

parti

cula

r pro

cedu

re, a

skin

g Le

vel 4

que

stio

ns m

ay b

e on

ly ef

ficac

y st

udy

poss

ible

.•

Inte

grat

ing n

egat

ive in

form

ation

abo

ut a

test

from

Lev

el 3

and

4 stu

dies

may

help

to d

irect

clin

ical u

se a

way

from

imag

ing

test

s th

at a

re n

ot u

sefu

l or h

ave

been

supp

lante

d by

oth

er te

sts.

• De

finitiv

e an

swer

re e

fficac

y wi

th re

spec

t to

patie

nt o

utco

me

requ

ires

RCT

(invo

lving

with

hold

ing

test

from

som

e pa

tient

s).

• RC

Ts m

ay b

e as

socia

ted

with

form

idab

le s

tatis

tical

, em

piric

al, a

nd e

thica

lpr

oble

ms

and

are

just

ified

only

in c

aref

ully

sele

cted

situ

atio

ns.

• W

eake

r evid

ence

may

be

deriv

ed fr

om c

ase

cont

rol s

tudie

s or

cas

e se

ries.

• In

depe

nden

t con

tribu

tion

of im

agin

g to

pat

ient

out

com

e m

ay b

e sm

all,

requ

iring

very

larg

e sa

mpl

e siz

es.

• De

cisio

n an

alyt

ic ap

proa

ch c

an b

e al

tern

ative

to R

CT, b

ut th

e an

alys

es m

ay s

uffe

rfro

m th

e sa

me

bias

es a

s th

eir s

econ

dary

dat

a so

urce

s.•

Decis

ion

anal

yses

can

hig

hlig

ht c

ritica

l pie

ces

of in

form

atio

n an

d gu

ide

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December 1998


2. Assess the quality of individual studies of diagnostic tests

Criteria for assessing the quality of a diagnostic test evaluation have been defined for usein evidence-based medicine (Haynes and Sackett, 1995). These criteria, listed below,will be applied to individual studies in the report. If the criteria are not met, the studywill generally be considered insufficiently rigorous to provide the basis for patient caredecisions. However, such studies often provide useful information on the technicalcharacteristics of a diagnostic test, or may provide information necessary to subsequentdiagnostic accuracy studies.

Evidence-based medicine criteria for evaluating studies of diagnosis

§ Clearly identified comparison groups, of which ≥ 1is free of the target disorder. § Either an objective diagnostic standard (e.g., a machine-produced laboratory result) or a contemporary clinical diagnostic

standard (e.g., a venogram for deep venous thrombosis) with demonstrably reproducible criteria for any subjectivelyinterpreted component (e.g:, report of better-than-chance agreement among interpreters).

§ Interpretation of the test without knowledge of the diagnostic standard result (no test review bias). § Interpretation of the diagnostic standard without knowledge of the test result (no diagnostic review bias).

Haynes and Sackett, 1995

Documentation of test accuracy does not translate into documentation that the test isclinically useful. Sensitivity and specificity, while not as dependent on prevalence ofdisease as predictive values, can be biased by differences in patient mix in the studypopulation and the patients on whom the test will be used in clinical practice (Sackett etal. 1991). A published study that does not supply valid information needed to calculateposttest probability of disease (i.e., predictive values or likelihood ratios) would not assistclinicians in interpreting its results, or taking action based on those results.

Evidence-based criteria provide a broad quality screen for clinicians who arecontemplating using a test in their own patients. A somewhat more detailed set of qualitycriteria, that expand on those of evidence-based medicine, have been used by theAmerican College of Physicians in evaluations of the literature on magnetic resonanceimaging (Kent et al., 1994; Kent and Larson, 1992; Kent and Larson, 1988). Thesecriteria were applied to studies of diagnostic accuracy and diagnostic thinkingefficacy.

December 1998


Methodologic quality of diagnostic accuracy studies

Grade CriteriaA Studies with broad generalizability to a variety of patients and no significant flaws in research

methods• ≥ 35 patients with disease and ≥ 35 patients without disease (since such numbers yield 95% CIswhose lower bound excludes 0.90 if Se = 1)

• patients drawn from a clinically relevant sample (not filtered to include only severe disease) whoseclinical symptoms are completely described

• diagnoses defined by an appropriate reference standard• PET studies technically of high quality and evaluated independently of the reference diagnosis

B Studies with a narrower spectrum of generalizability, and with only a few flaws that are welldescribed (and impact on conclusions can be assessed)• ≥ 35 cases with and without disease• more limited spectrum of patients, typically reflecting referral bias of university centers (more severeillness)• free of other methods flaws that promote interaction between test result and disease determination• prospective study still required

C Studies with several flaws in methods• small sample sizes• incomplete reporting• retrospective studies of diagnostic accuracy

D Studies with multiple flaws in methods• no credible reference standard for diagnosis• test result and determination of final diagnosis not independent (diagnostic review and/or test reviewbias)• source of patient cohort could not be determined or was obviously influenced by the test result(work-up bias)• opinions without substantiating data

Studies that assess the efficacy of diagnostic tests, particularly estimates of sensitivityand specificity, are susceptible to a variety of biases (Begg, 1987). Thornbury et al.(1991) described five aspects of research methodology that may influence accuracyestimates. Insufficient sample size may result in failure to detect differences betweenimaging modalities, if in fact they do exist, and may provide imprecise estimates ofimaging accuracy.

Differences among patient populations in the spectrum of disease presentation (case mix)and severity result in referral bias. The spectrum of patients needed to assess adiagnostic test will depend on the clinical situation. For example, at initial presentationof abnormality the spectrum should also include patients with no abnormality as well aspatients with abnormalities that may be confused with malignancy. For diagnosingrecurrent disease the spectrum should include patients with recurrence, patients with norecurrence, and patients with treatment changes that may be confused with malignancyon testing. A wider spectrum of patients would be needed to assess a test when there is ahigh prevalence of benign conditions (eg. SPN), whereas a test could be assessed in anarrower spectrum of patients with higher prevalence cancers.

Biases related to the appropriate use of a diagnostic reference standard are work up bias,test review bias, and diagnostic review bias. Presence of referral bias and referencestandard methodologic biases result in overestimation of true positive rates andunderestimation of false positive and negative rates.

December 1998


Considerable activity in the diagnostic testing literature is focusing on developing studydesigns and analytic techniques to correct for, or minimize the effect of, these biases.Some of the more common methods for limiting their influence on diagnostic accuracyestimates are presented below:

Biases in Studies of Diagnostic Imaging Tests

Type of bias Techniques to minimize bias Comments

Referral/spectrum

the influence of spectrum andseverity of disease (case mix)on test characteristics

• referral sources from a variety of medicalpractice settings in which potential patientsubjects are first encountered

• clearly defined referral• define patient groups based on physician’s pre-

test probability estimate of disease• adequate subgroup sizes

⇒ gives sufficient number and mixof patients needed to definepredictive values

⇒ can determine generalizability ofstudy results to own population

⇒ allows subgroup analysis ofdiagnostic accuracy estimates

Work-up/verification

• results from imaging testdetermine the choice ofpatient verified by the goldstandard, or

• study is restricted to biopsyverified cases

• all patients have all competing tests• prospective study in which all patients receive

definitive verification of disease status• sufficient follow-up time• retrospective adjustments• algebraic correction involving regression of

empirical disease frequencies against theprobability of disease as determined in apredictive model

⇒ magnitude of the bias is relatedto association between selectionfor verification and test result

⇒ maximizes diagnostic certainty⇒ require test results and

covariate data from the sourcepopulation and verified sample

Test review

imaging test interpretation is notindependent of final diagnosis,clinical information or results ofcomparison test

• randomized, blinded, independent interpretationof imaging test

• readings with and without clinical information• allow sufficient time between readings• standardize diagnostic terms and degrees of

abnormality• document impact of uninterpretable results• use multiple readers and determine

interobserver variability and methods forresolving differences

⇒ can determine effect of clinicalinformation on diagnosticprobability estimates

⇒ frequency of uninterpretability isan important consideration inthe cost-effectiveness of a test

Diagnostic review/incorporation

gold standard diagnosis is notindependent of imaging testresults

• extensive nodal sampling regardless of imagingresults

• expert interdisciplinary panel to review patientinformation and revise diagnostic and probabilityestimates incrementally

⇒ blinding practitioner to imagingmay be impractical , but effect ofbias can be minimized

⇒ panel process optimizes thefinal diagnosis in cases in whichbiopsy result is and is notavailable

Adapted from Begg (1987), Thornbury et al. (1991), and Webb et al. (1991)

3. Evaluate the strength of the evidence supporting a causal link between the useof the technology and improved outcomes of care

The third analytic framework for the literature review will rank the available evidence forthe degree to which it supports a causal link between the use of the technology andimproved outcomes. Recommendations about the use of a technology should be linked tothe quality of the available evidence, with the strength of the evidence dependent on thequality of the available evidence.

Several models for this framework exist that are based on well-established scientificprinciples of study design. Flynn (1996) used the model below by Cook (1992) tosummarize the relative strengths associated with various study designs and to rank the

December 1998


persuasiveness of their findings between the use of the technology and the outcome ofinterest:

Classifications of study designs and levels of evidence(when high quality meta analyses/overviews are not available)

Level Description

I Randomized trials with low false-positive (alpha) and low false-negative (beta) errors(high power)

• positive trial with statistically significant treatment effect (low alpha error)• negative trial that was large enough to exclude the possibility of a clinically important

benefit (low beta error/high power; i.e. had a narrow confidence interval around thetreatment effect, the lower end of which was greater than the minimum clinically importantbenefit)

• meta analysis can be used to generate a pooled estimate of treatment efficacy across allhigh quality, relevant studies and can reveal any inconsistencies in results

II Randomized trials with high false-positive (alpha) and/or high false negative (beta)

errors (low power) • trial with interesting positive trend that is not statistically significant (high alpha error)• negative trial but possibility of a clinically important benefit (high beta error/low power; i.e.

very wide confidence intervals around the treatment effect)• small positive trials with wide confidence intervals around the treatment effect, making it

difficult to judge the magnitude of the effect• when Level II studies are pooled (through quantitative meta analysis), the aggregate effects

may provide Level I evidence

III Nonrandomized concurrent cohort comparisons between contemporaneous patientswho did and did not (through refusal, noncompliance, contraindication, local practice,oversight, etc.) receive treatment • results subject to biases• Level III data can be subjected to meta analysis, but the result would not shift these data to

another Level, and is not usually recommended

IV Nonrandomized historical cohort comparison between current patients who didreceive treatment (as a result of local policy) and former patients (from the sameinstitution or from the literature) who did not (since at another time or in anotherinstitution different treatment policies prevailed) • results subject to biases, including those that result from inappropriate comparisons over

time and space

V Case series without control subjects • may contain useful information about clinical course and prognosis but can only hint at

efficacy

Source: Cook et al. (1992)

Ibrahim (1987) presented a similar framework to display the continuum of study designsand their causal implications.

December 1998


Continuum of study designs and their causal implications

Level* Study design Inference/strength of evidence

IRandomized controlled trials (RCT)Community randomized trialsSystematic reviews of RCTs

Firm

II Prospective cohort Moderately firm

III Before-after with controlsHistorical cohort Highly suggestive

IV Case-control Moderately suggestive

VTime seriesEcologic correlationsCross-sectional

Suggestive

VIAnecdoteClinical hunchesCase history

Speculative

Adapted from Ibrahim, (1985).*For simplicity, the numerical order was reversed for this review to align with the levels found in the previous table.

Levels IV, V, and VI are observational (nonexperimental) studies. Observational studies aresubject to many forms of bias, which can diminish the accuracy of their findings. They do notprovide strong evidence linking interventions with the observed outcomes; however, they can beuseful for generating hypotheses for future research. Levels II and III are considered quasi-experimental designs. They are commonly used in health care and provide stronger evidencethan can be obtained from observational studies. Level I studies are true experimental studiesand provide the most persuasive evidence for linking interventions with the observed outcomes.

Both frameworks will be used to appraise the strength of the evidence that links use of PET withdesired outcomes, particularly to effect change in diagnosis and treatment management.

December 1998


XV. APPENDIX 2

Models of High Quality Efficacy Studies of Diagnostic Imaging Technologies

Study Highlights of study design

Mushlin (1993)

MRI vs. CT in patients withsuspected multiple sclerosis

§ multi-site study with well-defined referral sources and filters, included patients with an uncertaindiagnosis, representing those in whom the tests might be used

§ sufficient sample size§ all patients receive all tests under evaluation§ independent, blinded image interpretation§ varying degrees of abnormality on the images were noted to permit calculation of receiver-operating

characteristics (ROC) analysis and likelihood ratios for summary comparisons§ sufficient follow-up to permit reasonable diagnostic certainty§ use of technology that is representative of what is available and widely used in most medical

communitiesStark (1987)

MRI vs. CT in patients diagnosedwith liver metastases

§ included patients with and without disease, and patients with benign disease commonly confused withmetastases

§ independent, blinded interpretation of each test and gold standard diagnosis§ used ROC analysis to permit comparison of tests over a range of confidence levels and diagnostic

thresholdsWebb (1991)

MRI vs. CT to determine extent ofdisease in patients with non-smallcell bronchogenic carcinoma

§ multi-site study with a detailed description of the filter through which patients entering into the studywere passed (to reduce referral bias)

§ data dichotomized to analyze lower and advanced stage disease§ blinded, independent interpretation of test results and interobserver variability calculated§ independent pathologic data available for all patients analyzed§ use of standardized forms for data analysis§ extensive nodal sampling not limited to abnormal results on imaging§ assessed influence of sampling procedure on results

Rifkin (1990)

MRI vs. transrectalultrasonography to determineextent of disease in surgicalcandidates with probablelocalized prostate cancer

§ large consecutive case series and a multi-site study§ used standardized forms for data analysis§ blinded, independent interpretation of test results using a five-point grading scale appropriate for ROC

analysis§ lesions identified on diagnostic imaging were matched with pathological findings using a computer

algorithm

Thornbury (1993)

MRI vs. plain CT vs. CTmyelography in patients withacute low-back pain and radicularpain

§ patients with a range of probability of disease were included, based on initial clinical diagnosis beforeimaging

§ sample size sufficient to provide reasonable statistical power§ MRI and one of the two CT tests were performed in all patients§ follow-up time sufficient to permit reasonable diagnostic certainty§ randomized, unpaired blinded interpretation of all tests§ use of an expert interdisciplinary panel to determine true diagnosis§ data collection provided information for use in a cost-effectiveness analysis

Zerhouni (1996)

CT vs. MRI in staging colorectalcarcinoma

§ multi-institutional study with well defined and described study population and referral filter§ all subjects received either histopathologic, follow-up verification, or corrected for work up bias using

technique of Gray et al (1984)§ well-defined positivity criteria§ blind, independent interpretation of each test compared to joint interpretation§ standardized surgical form for data collection of extent of disease for gold standard determination§ extensive quality control procedures to monitor data collection and compliance§ data analysis stratified based on pre-test knowledge of disease

December 1998


XVI. APPENDIX 3

Active Funded Research at VHA PET Facilities as of October 1, 1998

Site Study Title/Number Funding/Sponsor Start/CompletionDates

St. Louis 18F-Fluorodeoxyglucose (FDG) PositronEmission Tomography (PET) Imaging in theManagement of Patients with SolitaryPulmonary Nodules (CSP 27)

$2,306,632 – funded by VHA ORDCooperative Studies Program

1998/5 yearproject

Neurobehavioral Correlates of Mental StressIschemia (R01 HL59619-01A1)

$1,300,000 - NIH National Heart,Lung and Blood Institute

1998-2001

Psychological, CNS and MyocardialMechanisms in Mental Stress Ischemia

$374,000 - Merit Review Award 1998-2000

CNS Correlates of Mental Stress InducedMyocardial Ischemia in Women

$100,000 - Charles A. DanaFoundation, Neuroscience ResearchProgram on Brain-Body Interaction

Starts 1998,duration 3 years

Study to Determine the Effect of Atorvastatinon the Progression of Atherosclerosis

$210,000 - Parke-DavisPharmaceutical Research

1998-1999 (6-month project)

Impact of PET on Patient Care Algorithm $50,000 - funded by VHA Office ofPatient Care Services

1998-1999

PET Measurement of Cerebral Blood FlowCorrelates of Memory in Posttraumatic StressDisorder

$421,094 - Career DevelopmentAward

10/1/97-9/30/00

PET Measurement of Hippocampal Function(Memory) in Depression

$56,500 - National Alliance forResearch in Schizophrenia andDepression, Young Investigator Award

7/1/97-6/30/99

Cerebral Metabolic Correlates of AMPT-induced Depressive Relapse

$306,000 7/1/96-6/30/99

PET Measurement of Cerebral Blood FlowCorrelates of Traumatic Memory in PTSD

$850,000 per year ContinuingRenewal

Hippocampal Function in Gulf War Combat-related PTSD

$299,400 7/1/98-6/30/02

Hippocampus in Women with Abuse-relatedPTSD

$967,000 - NIMH 1/1/99-12/30/02

PET Measurement of BenzodiazepineReceptor in Anxiety

$850,000 per year - National Centerfor Posttraumatic Stress DisorderGrant

ContinuingRenewal

PET Measurement of Cerebral Blood FlowCorrelates of Conditioned Fear

$850,000 - National Center forPosttraumatic Stress Disorder Grant

ContinuingRenewal

Transmyocardial Laser Revascularization inChronic Canine Model of Ischemia

$80,000 - United States SurgicalCorp.

10/96-12/98

Dynamic SPECT BMIPP Imaging comparisonwith Perfusion and FDG Accumulation

$149,400 - Nihon Mediphysics 3/96-6/99

West Haven

PET Neuroreceptor Imaging (Serotonin-2Aand Serotonin-1A)

• $100,000 - National Institute ofMental Health Clinical ResearchCenter

• $55,000 - VA SchizophreniaResearch Center

• 10/1/96-9/30/01

• 10/1/94-12/31/99

Quantitative Assessment of FunctionalConnectivity in the Hereditary Ataxias (PO1NS33718)

$87,720 - Sponsored by NIH/NINDS 1/1/95-12/31/99

Spatial and Temporal Patterns in FunctionalNeuroimaging (P20 MH57180)

$1,113,418 - Sponsored by NIH $9/30/96-9/29/01

Correlation of Cholinergic Reserve andCognitive Function with Positron EmissionTomography (LOI-96-001)

$106,446 - With the Alzheimer’sAssociation

10/15/96-10/14/98

Motor Cortex and the Control of DynamicForce

$75,500 - Merit Review Award by VA 11/1/96-10/30/01

Minneapolis

Functional MRI of Human Motor Cortex(5RO1 NS32437-02)

$150,178 - Sponsored by NIH.NINDS 4/1/95-3/30/98

December 1998



Functional reorganization with cortical motorareas

$33,000 - Funded by Charles A. DanaFoundation

1/1/95-12/31/98

Neural mechanisms of drawing movementsunder different load conditions

$73,300 - Funded by the NationalScience Foundation

4/1/97-3/31/00

Optimizing 3D Iterative Reconstructions forPET (R29 NS33721)

$71,369 - Sponsored by NINDS 12/1/94-11/30/99

Regional FDG Uptake in Stunned vsHibernating Myocardium (R29 HL52157)

$78,012 - Sponsored by NIH/NHLBI 2/1/96-1/31/01

Quantitative Magnetic ResonanceAssessment of Microvascular Dysfunction(R01 HL58876)

$194,475 - Sponsored by NIH 9/1/97-8/31/00

Functional Anatomy of Human Cognition $99,000 - VA Merit Review Award 10/1/95-9/30/99PET studies of Lexical Processing inSchizophrenia

$30,000 - Young Investigator Awardfrom NARSAD

7/1/96-6/30/98

Lexical Processing in the DifferentialDiagnosis of Mania from Depression

$12,151 - Funded by MinnesotaMedical Foundation

4/1/98-3/31/99

PET Imaging of Hunger and Satiety $38,704 - Minnesota Obesity Center 8/1/96-7/31/97Hippocampal and Memory Dysfunction inNormal Aging

$29,700 - Alzheimer’s DiseaseAssociation

7/1/96-12/31/97

Positron Emission Tomographic Study ofTinnitus and Auditory Plasticity

$46,125 - American TinnitusAssociation

6/1/96-10/30/97

Positron Emission Tomographic Studies ofthe Auditory System

Jane H. Cummings Foundation 6/1/97

A Comparison of Cerebral Blood Flow inMigraineurs During Headache, HeadacheFree, and Treatment Periods

$114,300 - Department of Defense Start 7/1/95duration of twoyears

PET Studies of Temporal Mandibular JointPain

$20,000 - State University of NewYork

Start 6./1/97duration of oneyear

Glucose Transport in Stunned andHibernating Myocardium

$105,000 - New York State Affiliate,American Heart Association

7/1/97-6/30/00

Chronic Alterations in Glucose Transport inHibernating and Stunned Myocardium

$277,800 - American HeartAssociation

7/1/96-6/30/01

Chronic Adaptations to Myocardial Ischemia $1,120,447 - NIH and National HeartBlood and Lung Institute

PET Studies of Tinnitus and Hearing Loss $1,272,652 - NIH and NationalInstitute on Deafness andCommunicative Disorders

Starts 1/98duration of 5 years

Buffalo

PET Imaging subproject $48,240 - NIH and National Instituteof Aging

Fluoxetine Effects on Mood, Cognition &Metabolism

$507,446 - National Institute ofMental Health

Ends 8/31/98

Anterior Cingulate Metabolism in Depression $99,992 - NARSAD Ends 9/14/98Multimethodological Studies in CognitiveNeuroscience

$85,440 - Blue List Neurobiology Ends 12/31/98

The Role of PET in Conjunction with MaximalExercise Stress in Assessment of ChronicStable Coronary Artery Disease

$25,000 - Dupont Pharmaceuticals,Inc.

Ends 01/01/99

The Effects of Prozac Treatment on Mood,Cognition and Brain Glucose Metabolism inPatients with Primary Unipolar Depression

$49,940 - Eli Lilly and Co. Ends 01/01/99

PET/TMS Mapping of the Neural Circuitry ofDevelopmental Stuttering

$100,000 - Dan Foundation Ends 12/31/99

Interactive Effects of Mood and CognitionChallenges on Anterior Cingulate Function inRemitted Depression

$60,000 - NARSAD YoungInvestigator Award

Ends 06/30/00

Hunger for Air Study $140,000 - Mathers Foundation Ends 06/30/00

San Antonio

Investigating the Neural Bases of ChronicStuttering

$435,231 - NIH Ends 11/30/01

Indianapolis Role of Hemodynamics in In-Vivo InsulinResistance (R01 DK 42469)

$207,453 - sponsored by NIH 7/1/95-6/30/00

December 1998



SCOR in Sudden Cardiac Death (P50 DK52323)

$258,274 - sponsored by NIH 1/1/95-12/31/99

PET Imaging in the Surgical Management ofMelanoma

$127,918 - Sponsored by NIH 4/1/97-3/31/01

Effect of NIDDM on Glucose Transport intoSkeletal Muscle

Not available 1998

The Effect of Troglitazone, Metformin, andSulfonylurea on Insulin-stimulated GlucoseTransport and Phosphorylation, OxidativeEnzyme Capacity and Muscle Composition inNIDDM

Not available Ongoing

Echocardiographic Assessment of MyocardialViability in patients with Impaired LeftVentricular Function

Not available 1998

Pittsburgh

The Role of PET Scanning in Staging thePatient with Intrathoracic Malignancies: Non-small Cell Lung Cancer

Not available 1998

Pre-frontal Dysfunction in Frontal LobeEpilepsy

VA Merit Review

Psychiatric and Behavioral Disturbances inAlzheimer’s Disease

NIMH

The Study of Cognitive Processes in NormalIndividuals: Activation Studies of the NormalHuman Frontal Lobe

Mathers Charitable Foundation

Effect of Smoking on Coronary Blood FlowReserve and Attenuation Effect on CoronaryVasodilator Response of Nitroglycerine

California Tobacco Institute

Perception and Modulation of VisceralSensations

NIH and Astra Pharmaceuticals

Central Nervous System Processing ofSensory Information in Irritable BowelSyndrome (IBS) and Fibromyalgia

CAP

Functional Electrical Stimulation on SpinalCord Injured Patients

VA PM&R R&D

Evaluation of Limb Blood Flow with 15O-H20PET

VA PM&R R&D

15O-H 20 Scanning in Schizophrenia;Assessing Training-Related Improvement

Stanley Foundation and/or NARSADYoung Investigator Award

Brain Metabolic Changes with CigaretteCraving

California Tobacco institute

PET-FDG Imaging of Opioid DependentSubjects

NIDA

Pathogenesis of Symptomatic vs. SilentMyocardial Ischemia

Not Available

West LosAngeles

Assessment of Myocardial Viability Using PETto Determine Benefit for Revascularization

Not Available

Michigan Alzheimer’s Disease ResearchCenter

NIA

PET study of Biochemistry and Metabolism ofCNS

NIND&S

Forebrain Mechanisms of Pain and Analgesia $300,000 - VA Merit AwardForebrain Responses to Chronic Pain and ItsTreatment

NICH&HD

Concomitant Chemotherapy and Radiation forOrgan Preservation in Patients with Advanced(Stage III, IV) Laryngeal Cancer

University of Mich./VA

Ann Arbor

Combined Hormone Replacement Therapyand Myocardial Blood Flow

VA

December 1998



Effect of Conjugated Equine Estrogen andMicronized Progesterone on Coronary ArteryEndothelial Function as Assessed by PositronEmission Tomography

VA

Limbic Blood Flow & Opiate Receptor PET inPosttraumatic Stress Disorder

$288,500 - VA Merit Award

Paroxysmal Dystonia-Choreoathetosis NIND&SPET Studies of Dopaminergic Neurons inChronic Severe Alcoholism

NIAA&A

Metabolic Imaging of Renal Masses withPositron Emission Tomography

VA

Metabolic Imaging of Pancreatic Disease withPositron Emission Tomography

University of Mich./VA

Imaging of Intermediary Metabolism inNeoplasia using C-11 Acetate PET

VA

December 1998


Resu

lts/C

omm

ents

De

tect

ing

dise

ase

recu

rren

ce (w

ith 9

5% C

I) (2

1 po

sitiv

e ca

ses,

6 n

egat

ive

case

s)PE

T: S

e=90

% (7

7-10

0%);

Sp=8

3% (5

3-10

0%);

PPV=

95%

; NPV

=71%

; Acc

urac

y=89

%;

LR+=

5.43

; LR-

=0.1

1

Au

thor

s’ c

omm

ents

• PE

T m

ay b

e us

ed in

situ

atio

ns w

hen

sam

plin

g bi

as is

mor

e lik

ely

eg. d

ifficu

lt ac

cess

,qu

estio

nabl

e po

st-th

erap

y bi

opsy

resu

lts, o

r a n

orm

al, r

eepi

thel

ializ

ed a

ppea

ranc

e of

tum

orsit

e po

st-th

erap

y•

PET

scan

sho

uld

be o

btai

ned

befo

re b

iops

y to

avo

id p

ossib

le c

onfu

sing

effe

cts

of p

ost

biop

sy in

flam

mat

ion

or w

ait 5

-7 d

ays

afte

r nee

dle

biop

sy o

r 6 w

eeks

afte

r sur

gica

l res

ectio

n•

Posit

ive P

ET s

can

may

be

indi

cativ

e of

resid

ual t

umor

and

war

rant

repe

at ti

ssue

sam

plin

gor

rese

ctio

n•

Nega

tive

PET

scan

may

also

nec

essit

ate

tissu

e co

nfirm

atio

n to

rule

out

false

neg

ative

resu

lts

Patie

nts/

Met

hods

Purp

ose

To e

valu

ate

(?pr

ospe

ctive

ly) c

hem

othe

rapy

resp

onse

usin

g PE

T in

pat

ient

s wi

th a

dvan

ced

head

and

nec

k ca

ncer

Case

s28

con

secu

tive

patie

nts

with

Sta

ge II

I/IV

head

and

nec

k ca

ncer

who

wer

e pa

rticip

atin

g in

ane

oadj

uvan

t org

an-p

rese

rvat

ion

prot

ocol

usin

g ta

xol a

nd c

arbo

plat

in

Met

hods

• PE

T sc

ans

and

tissu

e bi

opsy

per

form

ed o

n al

l pat

ient

s be

fore

and

afte

r (1-

2 we

eks)

chem

othe

rapy

• Ti

ssue

obt

ained

afte

r 2 c

ours

es if

clin

ical r

espo

nse

by c

linica

l exa

m a

nd C

T wa

s <

50%

as

dete

rmin

ed b

y ch

ange

in p

rimar

y tu

mor

size

; and

afte

r 3 c

ours

es if

resp

onse

was

> 5

0%•

Blind

ed v

isual

cons

ensu

s an

alysis

of P

ET b

y tw

o re

ader

s us

ing a

bef

ore

and

afte

rco

mpa

rison

form

at o

n on

e pa

ge p

er p

atien

t usin

g a

4-po

int s

cale

• RO

Is m

easu

red

and

SURs

cal

cula

ted

corre

cted

for b

ody

weig

ht w

hile

blin

ded

to p

atho

logy

resu

lts•

Post

ther

apy

biop

sies

obta

ined

afte

r PET

blin

ded

to P

ET d

ata

• Pa

tient

s cla

ssifie

d as

pat

holo

gic

com

plet

e re

spon

se (P

CR) o

r res

idua

l dise

ase

(RD)

bas

edon

bio

psy

resu

lts

Lim

itatio

ns o

f stu

dy d

esig

n•

Smal

l sam

ple

size

• Sh

ort f

ollo

w up

tim

e•

No c

ompa

rison

dat

a pr

esen

ted

XV

II.

AP

PE

ND

IX 4

: D

ata

Abs

trac

tion

Tab

les

of I

nclu

ded

Dia

gnos

tic

Eff

icac

y St

udie

s of

FD

G-P

ET

in C

ance

r

Dia

gn

ost

ic E

ffic

acy

of

FD

G P

ET

in H

ead

an

d N

eck

Can

cer

Stud

y

Lowe

et a

l. (1

997)

(St.

Loui

s He

alth

Scie

nces

Cen

ter,

Miss

ouri)

December 1998


De

tect

ing

know

n pr

imar

y di

seas

e (3

1 po

sitiv

e ca

ses,

0 n

egat

ive

case

s)Al

l 31

prim

ary

mali

gnan

t tum

ors

were

det

ecte

d by

PET

as

hype

rmet

aboli

c ar

eas

Dete

ctin

g no

dal m

etas

tase

s (1

2 po

sitiv

e ca

ses,

4 n

egat

ive

case

s)PE

T: S

e=67

%CR

/MRI

: Se

=67%

Clin

ical e

xam

: Se

=58%

• 7

of 1

2 pa

tient

s wi

th in

volve

d no

des

had

clinic

ally

obvio

us n

odal

met

asta

ses;

all w

ere

ident

ified

by P

ET•

PET

ident

ified

1 of

5 p

atien

ts wi

th o

ccult

nod

al dis

ease

De

tect

ing

loca

l rec

urre

nce

(10

patie

nts

with

recu

rren

ces,

2 n

on re

curr

ence

s)PE

T co

rrectl

y ide

ntifie

d pr

esen

ce o

r abs

ence

of d

iseas

e in

all 1

2 pa

tient

sSe

=100

%

Dete

ctin

g no

dal r

ecur

renc

e (8

pos

itive

pat

ient

s, 5

neg

ativ

e pa

tient

s)PE

T: S

e=10

0%; S

p=10

0%CR

/MRI

: Se

=75%

; Sp=

80%

Clin

ical e

xam

: Se

=100

%; S

p=60

%

O

ther

find

ings

• Ab

norm

al u

ptak

e un

rela

ted

to m

alig

nanc

y wa

s ca

used

by

oste

omye

litis

of th

e m

andi

ble

follo

wing

den

tal e

xtra

ctio

n an

d su

rger

y pe

rform

ed w

ithin

2 m

onth

s of

PET

imag

ing.

Find

ings

did

not

affe

ct cl

inica

l man

agem

ent

• Ef

fect

s of

pos

t-bio

psy

infla

mm

atio

n on

imag

ing

uncle

ar.

Purp

oses

To p

rosp

ectiv

ely

eval

uate

prim

ary

dise

ase,

ear

ly no

dal m

etas

tase

s, a

nd re

curre

nt d

iseas

e in

patie

nts

head

and

nec

k ca

ncer

Ca

ses

54 c

onse

cutiv

e pa

tient

s wh

o pr

esen

ted

to h

ead

and

neck

clin

ics a

t bot

h ho

spita

ls fo

ras

sess

men

t of s

quam

ous

cell c

arcin

oma

(31

with

prim

ary

dise

ase,

23

with

sus

pect

edre

curre

nce

or re

sidua

l dise

ase)

• of

whic

h 16

had

nec

k dis

secti

ons

(N0=

8; N

1=4;

N2a

=2; N

2b=2

)

M

etho

ds•

All p

atie

nts

exam

ined

und

er a

nest

hesia

and

clin

ically

sta

ged

befo

re im

agin

g•

All s

uspi

cious

are

as o

f aer

odig

estiv

e tra

ct w

ere

biop

sied

• Al

l pat

ients

had

PET

and

anat

omic

imag

ing:

CT (n

=37)

; MRI

(n=1

3);

CT+M

RI (n

=4)

• Cl

inica

l ass

essm

ent,

CT, M

RI, P

ET e

valu

atio

n, a

nd h

istol

ogy

each

per

form

edin

depe

nden

tly•

Stan

dard

size

and

mor

phol

ogica

l crit

eria

use

d to

ass

ess

noda

l dise

ase

on C

T/M

RI

Li

mita

tions

of s

tudy

des

ign

• Sm

all s

ampl

e siz

es in

sub

grou

p an

alys

es•

High

sus

picio

n of

mal

igna

ncy

(refe

rral b

ias)

• O

nly

biop

sy v

erifie

d ca

ses

anal

yzed

(wor

k up

bia

s)•

Crite

ria fo

r pos

itive

PET

not d

efin

ed (p

oten

tial t

est r

evie

w bi

as)

• Bl

indi

ng u

ncle

ar (p

oten

tial t

est r

evie

w bi

as)

• PE

T da

ta a

nalys

is no

t ful

ly de

scrib

ed•

Ord

er o

f biop

sy a

nd im

aging

not

des

cribe

d.

Won

g et

al.

(199

7)(C

linica

l PET

Cent

re o

f Guy

’san

d St

. Tho

mas

’Ho

spita

ls, L

ondo

n,U

K)

December 1998


Resu

lts/C

omm

ents

Dete

ctin

g no

dal m

etas

tase

s (9

pos

itive

dis

sect

ions

, 15

nega

tive

diss

ectio

ns)

PET:

Se=

78%

; Sp=

100%

; PPV

=100

%; N

PV=8

8%; a

ccur

acy=

92%

CT:

Se=5

7%; S

p=90

%; P

PV=8

0%; N

PV=7

5%; a

ccur

acy=

76%

*tren

d in

incr

ease

d ac

cura

cy o

f PET

ove

r CT

(P =

0.1

1)PE

T +

CT:

Se=8

6%; S

p=10

0%; P

PV=1

00%

; NPV

=91%

; acc

urac

y=95

%

Oth

er fi

ndin

gs•

PET

accu

rate

ly de

tect

ed p

rese

nce

or a

bsen

ce o

f cer

vical

met

asta

ses

in a

ll 8 p

atie

nts

with

SCC

of th

e or

al c

avity

• In

5 p

atien

ts wi

th e

ither

car

cinom

a of

the

orop

hary

nx o

r hyo

phar

ynx

PET

corre

ctly

iden

tified

cer

vical

met

asta

ses

in tw

o of

four

pat

ient

s wi

th n

eck

met

asta

ses

Patie

nts/

Met

hods

Purp

ose

To a

sses

s re

trosp

ectiv

ely th

e cli

nical

effe

ctive

ness

of P

ET in

the

evalu

ation

of N

0 sta

ged

neck

patie

nts

with

squ

amou

s ce

ll can

cer (

SCC)

of t

he u

pper

aer

odig

estiv

e tra

ct

Case

s14

pat

ient

s wi

th N

0 di

seas

e (2

4 to

tal n

eck

diss

ectio

ns) o

n cli

nica

l exa

m:

• St

age

I=1;

Sta

ge II

=8; S

tage

III=

2; S

tage

IV=3

from

a la

rger

stu

dy o

f 116

con

secu

tive

patie

nts

diagn

osed

with

hea

d an

d ne

ck c

ance

r, of

whic

h:•

72 h

ad b

iops

y-pr

oven

SCC

• 26

und

erwe

nt n

eck

disse

ction

s

Met

hods

• Al

l pat

ients

had

com

plete

exa

m c

onsis

ting

of P

ET a

nd p

anen

dosc

opy

• Ni

ne p

atie

nts h

ad p

reop

erat

ive C

T•

All p

atie

nts

had

mod

ified

radi

cal n

eck

diss

ectio

ns w

ith re

mov

al o

f lev

els

1 to

V•

Path

olog

ic sp

ecim

ens

exam

ined

for n

umbe

r of n

odes

, pre

senc

e of

mal

igna

ncy,

and

extra

caps

ular

spre

ad.

• PE

T sc

ans

corre

late

d wi

th p

atho

logi

c re

sults

, site

of p

rimar

y tu

mor

, and

CT

Lim

itatio

ns o

f stu

dy d

esig

n•

Small

num

ber o

f cas

es•

Imag

ing

test

s in

fluen

ced

sele

ctio

n of

pat

ient

s fo

r sur

gery

and

nod

al s

ampl

ing

not d

escr

ibed

(wor

kup

bia

s)•

Thre

shold

s fo

r cha

racte

rizing

dise

ase

on im

aging

not

repo

rted

(pot

entia

l tes

t rev

iew b

ias)

• In

depe

nden

t blin

d ev

aluat

ion o

f tes

ts an

d go

ld sta

ndar

d no

t rep

orte

d (p

oten

tial t

est r

eview

bias

and

diag

nost

ic re

view

bias

)

Stud

y

Mye

rs e

t al.

(199

8)(S

UNY,

VA

Med

ical C

ente

r,Bu

ffalo

, NY)

December 1998


Resu

lts/C

omm

ents

Dete

ctin

g ax

illar

y ly

mph

nod

e in

volv

emen

t (44

pos

itive

cas

es, 8

0ne

gativ

e ca

ses)

PET:

Se=

100%

; Sp=

75%

%; P

PV=6

9%; N

PV=1

00%

• Re

ason

s fo

r fal

se p

ositiv

e re

sults

und

eter

min

ed

Oth

er fi

ndin

gs•

Wea

k co

rrela

tion

betw

een

DUR

of m

etas

tatic

axil

lary

lym

ph n

odes

and

tum

or s

ize a

nd b

etwe

en S

PF•

No c

orre

lation

bet

ween

DUR

and

tum

or g

rade

or h

istop

atho

logy

• Co

rrela

tion

betw

een

DUR

and

horm

one

rece

ptor

s wa

s un

dete

rmin

ed

Auth

ors’

com

men

ts•

False

pos

itive

findi

ngs

may

ben

efit

from

com

plem

enta

ry u

se o

flym

phos

cintig

raph

y•

Conf

irmat

ion

is ne

eded

to d

eter

min

e if

PET

shou

ld b

e co

nsid

ered

the

initia

l tes

t in

axilla

ry ly

mph

nod

es

Patie

nts/

Met

hods

Purp

ose

To s

tudy

PET

for s

tagi

ng a

xilla

ry ly

mph

nod

e m

etas

tase

s in

bre

ast c

ance

r

Case

s12

4 pa

tient

s wi

th n

ewly

diag

nose

d an

d hi

stol

ogica

lly p

rove

n br

east

can

cer w

ho w

ere

stud

ied

with

PET

prio

r to

ther

apy:

• St

age

I=65

; Sta

ge II

a=30

; Sta

ge II

b=23

; Sta

ge II

Ia=6

• Tu

mor

size

: < 1

cm=1

6; >

1cm

=49;

>2c

m=3

0; >

3cm

=29

• M

ixed

type

s- 8

2% in

vasiv

e du

ctal

car

cinom

a•

Hype

rglyc

emic

patie

nts

exclu

ded

• Ax

illary

sta

tus:

10

patie

nts

with

pos

itive

lymph

nod

es o

n cli

nica

l exa

m, 4

pat

ient

s on

mam

mog

raph

y

Met

hods

• Al

l pat

ients

had

ER a

nd P

R as

says

, DNA

flow

cyto

met

ry, S

PF, P

ET•

DUR

calcu

lated

for p

rimar

y an

d ax

illary

nod

e up

take

: DU

R 1-

3 fo

r met

asta

ses

and

≥ 3

for

prim

ary t

umor

• Q

ualita

tive

PET

read

as

posit

ive if

disc

rete

foca

l upt

ake

> ba

ckgr

ound

• Im

ages

read

by

expe

rienc

ed ra

diolog

ists,

final

read

by

nucle

ar m

ed p

hysic

ian fr

om h

ard

copy

and

video

mon

itor b

linde

d to

lym

ph n

ode

stat

us; r

eade

r awa

re o

f prim

ary

carc

inom

a•

All p

atie

nts

had

leve

l I d

issec

tion,

som

e ha

d Le

vel I

I, no

ne h

ad le

vel I

II•

Aver

age

# di

ssec

ted

node

s=20

(ran

ge 7

-39)

for t

rue

posit

ives;

16

(rang

e 7-

36) f

or tr

uene

gativ

es; 2

0 (ra

nge

9-46

) for

false

pos

itives

• Q

ualita

tive

PET

com

pare

d to

pat

holog

y•

20 p

atie

nts

with

false

pos

itive

resu

lts fo

llowe

d fo

r 1-2

yea

rs fo

r rec

urre

nce

• DU

R co

rrela

ted

with

tum

or s

ize, g

rade

and

hist

opat

holo

gy, S

PF, D

NA p

loid

y, a

nd h

orm

one

rece

ptor

s

Lim

itatio

ns o

f stu

dy d

esig

n•

Sour

ce p

opul

atio

n un

clear

; ?co

nsec

utive

ser

ies

(pot

entia

l ref

erra

l bia

s)•

Ord

er o

f tes

ting

uncle

ar•

Influ

ence

of P

ET re

sults

on

biops

y pr

oced

ure

uncle

ar (p

oten

tial d

iagno

stic

revie

w bia

s bu

tm

inim

ized

by e

xten

sive

noda

l sam

plin

g)

Dia

gn

ost

ic A

ccu

racy

Eff

icac

y S

tud

ies

of

FD

G P

ET

in

Bre

ast

Can

cer

Stud

y

Utec

h et

al.

(199

6)(U

niv.

of I

llinoi

s Co

llege

of

Med

icine

and

Dow

nsta

teCl

inica

l PET

Cen

ter,

Peor

ia,

Illino

is)

December 1998


Resu

lts/C

omm

ents

Dete

ctin

g ax

illar

y ly

mph

nod

e in

volv

emen

t (20

pos

itive

axi

lla, 3

2 ne

gativ

e ax

illa)

over

all

PET:

Se=

95%

; Sp=

66%

; PPV

=63%

; NPV

=95%

• fa

lse p

ositiv

es c

ause

d by

ext

ensiv

e sin

us h

istio

cyto

sis a

nd fa

t rep

lace

men

t, m

ildpla

smac

ytosis

, and

hem

oside

rin-la

den

mac

roph

ages

• fa

lse n

egat

ive lik

ely

due

to p

atie

nt’s

larg

e siz

e

Oth

er fi

ndin

gs•

Auth

ors

foun

d no

diffe

renc

es in

resu

lts b

etwe

en tw

o sc

anne

rs

Auth

ors’

com

men

ts•

PET

is ac

cept

able

for u

se a

s a

scre

enin

g te

st•

axilla

ry d

issec

tion

shou

ld b

e pe

rform

ed in

pat

ient

s wi

th p

ositiv

e PE

T sc

ans

toco

nfirm

met

asta

ses,

to d

eter

min

e th

e nu

mbe

r of l

ymph

nod

es in

volve

d, a

nd fo

rlo

cal c

ontro

l•

estim

ates

of $

120,

000

in c

ost s

avin

gs a

nd d

ecre

ased

mor

bidi

ty w

ould

hav

eoc

curre

d in

the

22 p

atie

nts

with

neg

ative

PET

sca

ns, b

ut n

o fo

llow

up d

ata

pres

ente

d to

con

firm

• in

clusio

n of

add

itiona

l inte

rpre

tive

crite

ria s

uch

as th

e pr

esen

ce o

f bila

tera

l axil

lary

activ

ity, i

nten

sity

and

exte

nt o

f acti

vity

may

help

impr

ove

spec

ificity

of a

xillar

y PE

Tin

the

futu

re

Stud

y inc

ludes

20

patie

nts

revie

wed

in 19

96 M

DRC

PET

repo

rt

Patie

nts/

Met

hods

Purp

ose

to p

rosp

ectiv

ely

eval

uate

FDG

-PET

as

a sc

reen

ing

test

for a

xilla

ry ly

mph

nod

em

etas

tase

s in

brea

st ca

ncer

Case

s50

pat

ient

s wi

th 5

2 ax

illary

diss

ectio

ns (2

pat

ient

s wi

th b

ilate

ral d

iseas

e)wh

o m

et th

e fo

llowi

ng in

clusio

n cr

iteria

:•

Age

≥ 30

yea

rs•

Ope

rable

bre

ast c

ance

r•

At le

ast l

evel

2 ax

illary

lym

ph n

ode

disse

ction

to b

e pe

rform

ed w

ithin

3 m

onth

s of

PET

• M

inim

um o

f 10

lymph

nod

es d

issec

ted

• Ab

ility

to fa

st fo

r at l

east

4 h

ours

Exclu

sion

crite

ria w

ere:

• Hi

stor

y of

ipsil

ater

al a

xilla

ry ly

mph

nod

e di

ssec

tion

• Pr

eope

rativ

e sy

stem

ic th

erap

y•

Prim

ary

tum

or <

5m

m•

Unin

terp

reta

ble

PET

scan

(2)

Fina

l prim

ary

tum

or s

tagi

ng:

T0=1

; T1=

31; T

2=17

; T3=

3

Met

hods

• Tr

ansm

ission

and

em

ission

PET

sca

ns o

btain

ed o

n tw

o sc

anne

rs (S

cand

itron

ixSP

3000

and

CTI

ECA

T EX

ACT)

• PE

T sc

ans

revie

wed

by tw

o in

depe

nden

t rea

ders

blin

ded

to a

ll inf

orm

atio

n ot

her

than

axil

la s

ide

• PE

T sc

ans

grad

ed o

n a

5-po

int L

ikert

scal

e fo

r pre

senc

e of

incr

ease

d FD

G u

ptak

ean

d sc

an q

uality

; disc

repa

ncie

s re

solve

d by

con

sens

us; s

core

s ≥

3 ar

e po

sitive

• Hi

stop

atho

logy

obt

aine

d; a

ll lym

ph n

odes

diss

ecte

d (a

vera

ge #

/pat

ient

=17)

• O

pera

ting

char

acte

ristic

s of

bot

h sc

anne

rs c

ompa

red

Lim

itatio

ns o

f Stu

dy D

esig

n•

Patie

nt s

ourc

e un

clear

; ?co

nsec

utive

ser

ies

(pot

entia

l ref

erra

l bia

s)•

Asso

ciatio

n be

twee

n te

st re

sult

and

gold

sta

ndar

d de

term

inat

ion

uncle

ar (p

oten

tial

diag

nost

ic re

view

bias

min

imize

d by

ext

ensiv

e no

dal s

ampl

ing)

• No

follo

w-up

dat

a pr

esen

ted

• Au

thor

s us

ed h

igher

dos

e of

FDG

and

long

er s

cann

ing ti

mes

than

in o

ther

stu

dies

Stud

y

Adle

r et a

l. (1

997)

(Uni

vers

ity H

ospi

tals

and

Case

Wes

tern

Res

erve

Uni

vers

ity,

Clev

elan

d, O

hio)

December 1998


Resu

lts/C

omm

ents

Dete

ctin

g ax

illar

y no

de in

volv

emen

tN0

dise

ase

(10

posit

ive a

xilla

, 26

nega

tive

axilla

)PE

T: S

e=70

%; S

p=92

%; a

ccur

acy=

86%

N1a

dise

ase

(8 p

ositiv

e ax

illa, 1

3 ne

gativ

e ax

illa)

PET:

Se=

87.5

%; S

p=10

0%; a

ccur

acy=

95%

N1b-

2 (9

pos

itive

axilla

, 6 n

egat

ive a

xilla

)PE

T: S

e=10

0%; S

p=67

%; a

ccur

acy=

87%

over

all (

27 p

ositiv

e ax

illa, 4

5 ne

gativ

e ax

illa)

PET:

Se=

85%

; Sp=

91%

; acc

urac

y=89

%; P

PV=8

5%; N

PV=9

1%•

false

pos

itives

due

to v

ascu

lar u

ptak

e an

d un

dete

rmine

d ca

uses

• fa

lse n

egat

ives

due

to m

icros

copi

c an

d un

expl

aine

d m

acro

scop

ic in

volve

men

t,m

ean

size=

6mm

(5-8

mm

)

Oth

er fi

ndin

gs•

Med

ian

SUV

in c

arcin

omas

with

axil

lary

met

asta

ses

(4.6

) was

hig

her t

han

that

in ca

rcino

mas

with

out a

xillar

y m

etas

tase

s (2

.9),

but t

here

was

a s

ignific

ant

over

lap

betw

een

the

two

grou

ps (i

nter

quar

tile ra

nges

= 2.

7-7.

2 an

d 1.

9-4.

5,re

spec

tivel

y)•

ROC

anal

ysis

show

ed b

est c

utof

f val

ue o

f SUV

(2.9

) was

ass

ocia

ted

with

aSe

=74%

and

Sp=

58%

• An

y ch

ange

in re

ading

of R

OC

curv

e wa

s no

t use

ful in

pat

ient m

anag

emen

tre

ferre

d fo

r ALN

D•

Auth

ors

prop

ose

usin

g PE

T in

pat

ient

s wi

th v

ery

low

prob

abilit

y of

axil

lary

met

asta

ses

(t1a)

, in

whom

axil

lary

sur

gery

may

be

avoi

ded,

to m

onito

rre

lapse

s•

SUV

value

of p

rimar

y no

t a p

rogn

ostic

indic

ator

of a

xillar

y sp

read

Patie

nts/

Met

hods

Purp

ose

to e

valua

te p

rosp

ectiv

ely n

oninv

asive

sta

ging

of a

xillar

y no

des

using

PET

for m

etas

tase

s

Case

s68

con

secu

tive

patie

nts

with

pal

pabl

e br

east

nod

ules

(uni

late

ral d

iseas

e=64

; bila

tera

l=4)

who

were

sch

edul

ed fo

r bre

ast s

urge

ry w

/ or w

/o A

LND

base

d on

clin

ical a

nd in

stru

men

tal

(mam

mog

raph

y an

d/or

ultr

ason

ogra

phy)

resu

lts•

61 w

ith A

LND

with

72

tota

l axil

la s

ampl

ed: N

0=36

; N1a

=21;

N1b

=13;

N2=

2•

11 w

ith n

o AL

ND w

ere

class

ified

as n

egat

ive•

tota

l # b

reas

t nod

ules=

81 (7

3 m

align

ancie

s, 8

benig

n): T

1=45

; T2=

30; T

3=2;

T4=

4-

63%

of m

alig

nanc

ies

were

infilt

ratin

g du

ctal

car

cinom

as-

benig

n co

nditio

ns w

ere

proli

fera

tive

dysp

lasia

with

out a

typica

or f

ocal

inflam

mat

ion-

aver

age

size

= 20

mm

(4m

m-6

7mm

)

Met

hods

• PE

T em

ission

and

tran

smiss

ion s

cans

per

form

ed 1

to 7

day

s be

fore

sur

gery

• PE

T vis

ual in

terp

reta

tion

blind

ed to

hist

opat

holog

y; loc

alize

d up

take

> s

urro

undin

gtis

sue

class

ified

as p

ositiv

e•

Mea

n SU

Vs o

f bre

ast c

arcin

oma

were

cal

cula

ted

• RO

C an

alys

is pe

rform

ed u

sing

SUVs

bet

ween

two

grou

ps to

ass

ess

SUV

as a

prog

nost

ic in

dica

tor

• Av

erag

e #

diss

ecte

d no

des/

axilla

=21

(rang

e 12

-38)

• No

trea

tmen

t dec

ision

s m

ade

on th

e ba

sis o

f PET

Lim

itatio

ns o

f stu

dy d

esig

n•

High

inde

x of

sus

picio

n of

mal

igna

ncy

(refe

rral b

ias,

min

imize

d by

usin

g co

nsec

utive

serie

s)•

Blin

ding

of r

eade

rs to

oth

er c

linica

l info

rmat

ion

not r

epor

ted

(pot

entia

l tes

t rev

iew

bias

)•

Diag

nosti

c re

view

bias

mini

mize

d by

exte

nsive

nod

al sa

mpli

ng•

PET

used

in te

st se

quen

ce, i

ncre

men

tal v

alue

not a

sses

sed

Stud

y

Crip

pa e

t al.

(199

8)(N

ation

al Ca

ncer

Insti

tute

,M

ilan,

Ital

y)

December 1998


Resu

lts/C

omm

ents

Dete

ctin

g un

know

n pr

imar

y (1

3 m

alig

nant

tum

ors,

7 b

enig

n tu

mor

s)PE

T: S

e=92

%; S

p=86

%SM

M:

Se=9

2%; S

p=86

%•

calcu

lation

s ex

clude

d 2

recu

rrenc

es•

false

pos

itives

due

to fi

broa

deno

ma

• fa

lse n

egat

ives

due

to lo

cal r

ecur

renc

es w

ith d

iam

eter

s <

9mm

Axill

ary

node

invo

lvem

ent

(5 p

ositi

ve p

atie

nts,

7 n

egat

ive

patie

nts)

• PE

T co

rrectl

y de

tecte

d ax

illary

invo

lvem

ent i

n all

12

patie

nts

• (3

0 po

sitive

nod

es)

• PE

T de

tecte

d 9

of 3

0 no

des

• SM

M d

etec

ted

8 of

30

node

s

Qua

ntita

tive

anal

ysis

PET:

mea

n SU

V=2.

57 (0

.3-6

.2 w

ith m

edia

n SU

V=1.

6)SM

M:

mea

n TN

R=1.

97 (1

.42-

3.1

with

med

ian

TNR=

1.8)

Auth

ors’

com

men

ts•

Men

stru

al c

ycle

may

alte

r MIB

I upt

ake

in n

orm

al ti

ssue

• Di

ffuse

FDG

upt

ake

in n

orm

al tis

sue

decli

nes

with

age

• Th

resh

olds

and

var

iatio

ns in

SUV

cal

cula

tions

can

impa

ct te

st c

hara

cter

istics

• Bo

th te

sts c

ould

dete

ct ax

illary

nod

e inv

olvem

ent b

ut n

ot e

xtent

of d

iseas

e•

Larg

er c

ohor

t nee

ded

to c

onfir

m re

sults

Patie

nts/

Met

hods

Purp

ose

to c

ompa

re p

rosp

ectiv

ely

the

diag

nost

ic ac

cura

cy o

f FDG

PET

vs.

scin

timam

mog

raph

y(S

MM

) (pla

nar a

nd s

ingle-

phot

on e

miss

ion to

mog

raph

y) u

sing

99m T

c MIB

I

Case

s20

pat

ients

with

22

susp

iciou

s pr

imar

y les

ions

dete

cted

by P

E or

mam

mog

raph

ysc

hedu

led fo

r exc

ision

al bio

psy

• 14

pat

ient

s wi

th 1

5 m

alig

nant

prim

ary

lesio

ns (i

nclu

ding

2 lo

cal r

ecur

renc

es);

mea

nsiz

e 29

mm

(ran

ge 8

-53m

m);

3 pa

tient

s wi

th tu

mor

s ≤

8mm

• 5

patie

nts

with

30

axilla

ry n

ode

met

asta

ses

(all d

iam

eter

s ≥

12m

m)

Met

hods

• SM

M fo

llowe

d by

PET

sca

ns o

f bre

asts

and

axilla

ry re

gions

wer

e pe

rform

ed >

24

hrs

apar

t in

all p

atie

nts

durin

g th

e we

ek p

rior t

o su

rger

y•

ROIs

ana

lyzed

, M

IBI T

NR o

n pl

anar

imag

es a

nd S

UV F

DG u

ptak

e ca

lcula

ted

• M

amm

ogra

ms

used

for s

cintig

raph

ic lo

caliz

atio

n•

Foca

l upt

ake

class

ified

as n

orm

al o

r abn

orm

al•

Inde

pend

ent,

blin

ded

inte

rpre

tatio

n of

SM

M a

nd P

ET b

y tw

o nu

clear

med

icine

phys

ician

s•

PET

and

SMM

resu

lts e

ach

com

pare

d wi

th h

istop

atho

logy

Lim

itatio

ns o

f stu

dy d

esig

n•

Smal

l size

• Hi

gh in

dex

of s

uspi

cion

for m

alig

nanc

y (p

oten

tial r

efer

ral b

ias)

• Ex

tent

of b

lindi

ng to

oth

er c

linica

l info

rmat

ion

not c

lear

(pot

entia

l tes

t rev

iew

bias

)•

Asso

ciatio

n be

twee

n te

st re

sult

and

gold

sta

ndar

d de

term

inat

ion

uncle

ar (p

oten

tial

diag

nost

ic re

view

bias

)•

Incr

emen

tal v

alue

of t

est u

sed

in w

ork

up n

ot a

sses

sed

Stud

y

Palm

edo

et a

l. (1

997)

(Uni

vers

ity o

f Bon

n, G

erm

any)

December 1998


Resu

lts/C

omm

ents

Dire

ct v

isua

l com

paris

on (6

3 pa

tient

s av

aila

ble

for d

irect

com

paris

on)

Loca

l rec

urre

nce

(15

posi

tive

lesi

ons,

48

nega

tive

lesi

ons)

PET:

Se=

73%

; Sp=

96%

; PPV

=85%

; NPV

=92%

; Acc

=90%

CT/M

RI: S

e=91

%; S

p=98

%; P

PV=9

1%; N

PV=9

8%; A

cc=9

7%

Lym

ph n

odes

(22

posi

tive

lesi

ons,

41

nega

tive

lesi

ons)

PET:

Se=

95%

; Sp=

93%

; PPV

=88%

; NPV

=97%

; Acc

=94%

CT/M

RI: S

e=74

%; S

p=95

%; P

PV=8

9%; N

PV=8

7%; A

cc=8

8%(d

iscre

panc

ies

in to

tal n

umbe

rs o

f PET

lesio

ns v

s. to

tal n

umbe

r of C

T/M

RI le

sions

)

Bone

(13

posi

tive

lesi

ons,

50

nega

tive

lesi

ons)

PET:

Se=

100%

; Sp=

96%

; PPV

=87%

; NPV

=100

%; A

cc=9

7%CT

/MRI

: Se=

46%

; Sp=

98%

; PPV

=88%

; NPV

=86%

; Acc

=87%

Lung

(6 p

ositi

ve s

ites,

57

nega

tive

site

s; in

5 p

atie

nts)

• PE

T ha

d 2

false

pos

itive*

and

1 fa

lse n

egat

ive re

sults

• CT

/MRI

had

2 fa

lse p

ositiv

e an

d 1

false

neg

ative

resu

lts•

Reas

ons

for C

T/M

RI fa

lse p

ositiv

es n

ot re

porte

d

Live

r (2

posi

tive

site

s, 7

3 ne

gativ

e si

tes;

in 2

pat

ient

s)•

PET

had

one

false

pos

itive*

resu

lt an

d no

false

neg

ative

resu

lts•

CT/M

RI h

ad 1

false

pos

itive

and

1 fa

lse n

egat

ive re

sult

• *d

ue to

arti

fact

wro

ngly

inte

rpre

ted

durin

g th

e le

arni

ng p

hase

of t

he fa

cility

Auth

ors’

com

men

ts•

PET

and

CT/M

RI h

ad s

imila

r res

ults

re lu

ng a

nd liv

er m

etas

tase

s•

CT/M

RI id

entifi

ed m

ore

loca

l rec

urre

nces

cor

rect

ly•

PET

iden

tified

1/3

mor

e pa

tient

s wi

th ly

mph

nod

e m

etas

tase

s, s

ugge

stin

g th

e us

eof

PET

ear

ly in

resta

ging

of b

reas

t can

cer.

• Se

miqu

antita

tive

analy

sis a

nd tu

mor

app

eara

nce

info

may

dec

reas

e nu

mbe

r of

false

pos

itive

resu

lts•

Resu

lts s

ugge

st th

e im

porta

nce

of P

ET a

s a

com

plem

ent t

o m

orph

olog

ic te

sts

inth

e st

agin

g of

recu

rrenc

e•

PET

may

also

play

a ro

le in

whole

bod

y sta

ging

of h

igh ri

sk p

atien

ts•

Furth

er s

tudi

es a

re n

eede

d to

ass

ess

the

clini

cal im

pact

of P

ET in

the

man

agem

ent o

f rec

urre

nt b

reas

t can

cer a

nd it

s co

nseq

uenc

e on

ove

rall s

urviv

al

Patie

nts/

Met

hods

Purp

ose

To a

sses

s th

e fe

asib

ility

of P

ET in

sta

ging

recu

rrent

bre

ast c

arcin

oma

Case

s75

pat

ient

s wi

th s

uspe

cted

recu

rrent

or w

ith m

etas

tatic

dise

ase

in u

ndec

ided

or

equiv

ocal

case

s•

prim

ary

tum

or h

istol

ogy:

wel

l-diff

eren

tiate

d du

ctal

car

cinom

a (n

=46)

; inf

iltrat

ing

lobu

lar c

arcin

oma

(n=1

0)•

all p

atien

ts ha

d PE

T; 6

3 pa

tient

s ha

d PE

T an

d CT

/MRI

of w

hich:

- 14

pts

with

con

firm

ed lo

cal r

ecur

renc

e; 1

7 pt

s w/

con

firm

ed ly

mph

nod

e m

ets

• no

recu

rrenc

e (N

=15)

; loc

al re

curre

nce

(N=2

0); l

ymph

nod

e in

volve

men

t (N=

28);

dist

ant m

etas

tase

s (N

=22)

Met

hods

• Al

l pat

ients

had

rout

ine w

ork-

up c

onsis

ting

of p

hysic

al ex

am, a

xillar

y lym

ph n

ode

US, o

ptio

nal t

hora

x/ab

dom

en C

T an

d/or

MRI

, bon

e sc

intig

raph

y an

d se

rum

tum

orm

arke

rs•

All h

ad h

istol

ogic

conf

irmat

ion

(sur

gery

or b

iops

y), e

xcep

t 4 b

y fo

llow-

up•

PET

eval

uate

d qu

alita

tivel

y us

ing

a 4-

poin

t sca

le (i

nten

se, m

oder

ate,

low,

non

e)•

Two

read

ers

of P

ET n

ot b

linde

d to

ava

ilabl

e da

ta•

PET

com

pare

d ind

epen

dent

ly to

eac

h of

the

stand

ard

imag

ing m

odali

ties

• Al

l pat

ient

s fo

llowe

d fo

r at l

east

6 m

onth

s (1

-2 v

isits

)

Lim

itatio

ns o

f stu

dy d

esig

n•

Small

stu

dy s

ize in

sub

grou

p an

alyse

s•

High

inde

x of

sus

picio

n fo

r mal

igna

ncy

(pot

entia

l ref

erra

l bia

s)•

Patie

nt in

clusio

n ba

sed

in pa

rt on

resu

lts o

f CT/

MRI

(wor

k up

bias

but

mini

mize

d by

all p

atie

nts

rece

iving

def

initiv

e di

seas

e ve

rifica

tion)

• In

terp

reta

tion

of P

ET re

sults

not

blin

ded

to o

ther

clin

ical a

nd im

agin

g da

ta; p

ositiv

itycr

iteria

not

def

ined

(tes

t rev

iew

bias

)•

Asso

ciatio

n be

twee

n te

st re

sult

and

gold

sta

ndar

d de

term

inat

ion

uncle

ar (p

oten

tial

diag

nost

ic re

view

bias

)

Stud

y

Bend

er e

t al.

(199

7)(U

nive

rsity

of B

onn,

Ger

man

y)

December 1998


Resu

lts/C

omm

ents

Ove

rall

diag

nost

ic a

ccur

acy

(29

posi

tive

case

s, 2

8 ne

gativ

e ca

ses)

Scor

es ≥

4 d

efin

ed a

s po

sitiv

ePE

T: S

e=93

%; S

p=79

%; P

PV=8

2%; N

PV=9

2%Sc

ores

≥ 3

def

ined

as

posi

tive

PET:

Se=

93%

; Sp=

61%

; PPV

=82%

; NPV

=92%

Ove

rall

diag

nost

ic a

ccur

acy

(41

posi

tive

lesi

ons,

39

nega

tive

lesi

ons)

Scor

es ≥

4 d

efin

ed a

s po

sitiv

ePE

T: S

e=85

%; S

p=79

%; P

PV=8

1%; N

PV=8

4%Sc

ores

≥ 3

def

ined

as

posi

tive

PET:

Se=

90%

; Sp=

54%

; PPV

=67%

; NPV

=84%

ROC

anal

ysis

Az=0

.91

for p

atie

nt d

etec

tion;

Az=

0.88

for l

esion

det

ectio

n

Inte

robs

erve

r var

iabi

lity

• In

48%

of p

atie

nts,

sco

res

of a

ll 3 o

bser

vers

wer

e th

e sa

me

• In

38%

of p

atien

ts, a

sco

re fr

om o

ne re

ader

dev

iated

one

sco

re g

rade

from

the

othe

r 2 re

ader

s•

In 1

4% o

f pat

ients,

a s

core

from

1 re

ader

dev

iated

mor

e th

an 1

sco

re g

rade

from

the

othe

rre

ader

s

Oth

er fi

ndin

gs•

Bone

met

asta

ses

had

a la

rger

pro

porti

on o

f fal

se-n

egat

ive le

sions

than

oth

er m

alig

nant

site

swh

en s

core

s of

4 o

r 5 w

ere

rega

rded

as

posit

ive; B

one

Se=6

9% (1

1 of

16)

vs.

Non

-bon

eSe

=96%

(24

of 2

5) (p

<0.0

5)•

False

neg

ative

lesio

ns (s

core

d ≥

4) in

clude

d 5

bone

met

asta

ses

and

one

small

bre

ast s

ite, o

fwh

ich 3

bon

e an

d on

e br

east

lesion

sho

wed

mild

upt

ake

(sco

red

2-3)

, one

lesio

n wa

s co

nfirm

edpo

sitive

on

follo

w up

PET

sca

n•

Whe

n sc

ores

of ≥

3 w

ere

rega

rded

as

posit

ive, l

ymph

nod

e sit

es h

ad m

ore

false

pos

itives

than

othe

r site

s; L

ymph

Sp=

13%

vs.

Oth

er S

p=79

% (p

<0.0

5); w

ith s

core

s ≥

4, L

ymph

Sp=

60%

vs.

Oth

er S

p=92

% (p

<0.0

01)

• PP

V=62

% fo

r les

ions

with

a s

core

of 4

and

PPV

=90%

for l

esio

ns w

ith a

sco

re o

f 5•

False

pos

itive

lesio

ns (s

core

d ≥

3) w

ere

attri

bute

d to

mus

cle u

ptak

e, in

flam

mat

ion,

and

phys

iolo

gica

l and

arti

fact

ual F

DG u

ptak

e, a

nd u

nkno

wn c

ause

s•

Char

acte

ristic

s of

5 p

atien

ts wi

th fa

sting

bloo

d glu

cose

leve

ls >

110

mg/

dl: 4

diab

etics

, 2re

ceive

d ins

ulin,

3 w

ere

true

nega

tive,

one

true

pos

itive.

Auth

ors’

com

men

ts•

Mor

e st

rict a

ttent

ion

to p

atie

nt p

repa

ratio

n, re

cogn

ition

of a

rtifa

ctua

l upt

akes

, and

info

rmat

ion

oncli

nica

l hist

ory

(re in

flam

mat

ory

dise

ase)

will

impr

ove

spec

ificity

of P

ET•

Lim

itatio

ns o

f stu

dy: s

tudy

bia

sed

towa

rd p

ositiv

e le

sions

and

mor

e di

fficul

t cas

es, n

ot a

llre

gion

s we

re p

rosp

ectiv

ely

exam

ined

with

oth

er c

onve

ntio

nal im

agin

g st

udie

s•

Atte

nuat

ion

corre

ctio

n wo

uld

prov

ide

a m

ore

accu

rate

repr

esen

tatio

n of

trac

er d

istrib

utio

n•

A pr

ospe

ctive

stu

dy is

nee

ded

to fu

rther

ass

ess

the

role

of P

ET in

pos

t-sur

gical

brea

st ca

ncer

man

agem

ent

Patie

nts/

Met

hods

Purp

ose

To re

trosp

ectiv

ely

eval

uate

the

diag

nost

ic ac

cura

cy o

f PET

in p

atie

nts

with

susp

ecte

d re

curre

nt o

r met

asta

tic b

reas

t can

cer

Case

s57

fem

ale

patie

nts

with

83

refe

renc

e sit

es (2

9 wi

th d

iseas

e, 2

8 no

recu

rrenc

eor

met

asta

ses)

• wh

o un

derw

ent p

rimar

y su

rger

y wi

th o

r with

out a

djuv

ant c

hem

o- o

rra

diat

ion

ther

apy a

nd•

who

were

refe

rred

to th

e UC

LA P

ET c

ente

r fro

m O

ctob

er 1

990

to O

ctob

er19

95 (m

ean

time

inter

val b

etwe

en d

iagno

sis a

nd P

ET s

can=

4 yr

s. ra

nge

1m

o. T

o 17

yr 9

mo)

• wh

o ha

d a

clinic

al su

spici

on o

f dise

ase

recu

rrenc

e no

t res

olved

by

conv

entio

nal i

mag

ing

exclu

ded

case

s:•

patie

nts

who

unde

rwen

t che

mo-

or ra

diat

ion

ther

apy

with

in 3

mo

befo

rePE

T•

lesio

ns th

at w

ere

biop

sied

• les

ions

diagn

osed

with

kno

wn d

iseas

e

Met

hods

• Al

l pat

ients

unde

rwen

t hist

ory

and

PE, m

ultipl

e lab

s an

d im

aging

tests

• Di

agno

stic

conf

irmat

ion b

ased

on

biops

y, les

ion m

orph

ology

for t

umor

on

2 or

mor

e im

agin

g st

udie

s, a

nd fo

r at l

east

6 m

onth

s cli

nica

l and

radi

ogra

phic

follo

w up

• PE

T ab

norm

alitie

s th

at re

solve

d wi

thou

t tre

atm

ent w

ere

cons

ider

ed to

be

false

-pos

itive

resu

lts•

ECAT

931

and

ECA

T 96

1 we

re u

sed

• In

depe

nden

t visu

al in

spec

tion

of P

ET b

y 3

read

ers

info

rmed

clin

ical

susp

icion

of m

etas

tase

s, b

ut b

linde

d to

gol

d st

anda

rd; d

iscre

panc

ies

reso

lved

by 4th

read

er a

ware

of a

disc

repa

ncy

but n

ot o

f spe

cifics

• PE

T im

ages

sco

red

from

1 (d

efin

itely

nega

tive)

to 5

(def

inite

ly po

sitive

)•

Lesio

n sit

e de

fined

as

any

abno

rmali

ty su

gges

ting

the

poss

ibly

of b

reas

tre

curre

nce

or m

etas

tase

s eit

her c

linica

lly o

r on

imag

ing, t

here

fore

,an

alysis

was

bias

ed to

ward

pos

itive

lesion

s•

Analy

sis b

y pa

tient

and

by

lesion

Lim

itatio

ns o

f stu

dy d

esig

n•

Onl

y m

ore

diffic

ult c

ases

inclu

ded

and

susp

iciou

s sit

es a

sses

sed

(refe

rral

bias

)•

Not a

ll reg

ions

wer

e pr

ospe

ctive

ly ex

amin

ed w

ith o

ther

con

vent

iona

lim

agin

g te

sts

• Pa

rtial

blin

ding

(pot

entia

l tes

t rev

iew

bias

)•

Blin

ding

of g

old

stan

dard

dia

gnos

is (c

onfir

mat

ion)

to P

ET re

sults

unc

lear

(pot

entia

l dia

gnos

tic re

view

bias

)

Stud

y

Moo

n et

al.

(199

8)(U

CLA,

Los

Ang

eles

, Cal

iforn

iaan

d Un

ivers

ity o

f Ulsa

n, S

eoul

,Ko

rea)

December 1998


Resu

lts/C

omm

ents

Defin

ing

know

n pr

imar

y di

seas

e (1

09 c

ases

)•

all p

rimar

y tu

mor

s sh

owed

incr

ease

d fo

cal F

DG u

ptak

e; in

tens

e in

101

case

s, m

oder

ate

in 8

cas

es•

no c

orre

latio

n be

twee

n hi

stop

atho

logy

and

FDG

upt

ake

Med

iast

inal

invo

lvem

ent (

34 p

ositi

ve c

ases

, 32

nega

tive

case

s)PE

T: S

e=89

% (9

5% C

I: 72

-96%

); Sp

=87%

(95%

CI:

71-9

7%);

PPV=

89%

(

95%

CI:7

2-96

%);

NPV=

87%

(95%

CI:

71-9

6%);

accu

racy

=88%

CT:

Se=7

9%; S

p=71

%; P

PV=7

5%; N

PV=7

6%; a

ccur

acy=

75%

(no

95%

CI re

porte

d)•

disag

reem

ent b

etwe

en P

ET a

nd C

T in

29 c

ases

(44%

); co

rrect

chan

ges

by P

ET=2

2 ca

ses

(33%

); co

rrect

cha

nges

by

CT=7

(11%

)

Dist

ant m

etas

tase

s (3

9 po

sitiv

e ca

ses,

70

nega

tive

case

s)PE

T: S

e=10

0% (9

5% C

I: 9

1-10

0%);

Sp=9

4% (9

5% C

I: 86

-98%

);PP

V=90

% (9

5% C

I: 7

8-97

%);

NPV=

100%

(95%

CI:

95-

100%

);ac

cura

cy=9

6% (9

5% C

I: 9

0-98

%)

CI: S

e=82

%; S

p=89

%; P

PV=8

0%; N

PV=8

9%; a

ccur

acy=

86%

(95%

CI

not r

epor

ted)

• m

oder

ate

FDG

upt

ake

in 7

of 8

cas

es w

ere

< 2

cm.

• PE

T fa

lse p

ositiv

es c

ause

d by

non

spec

ific in

flam

mat

ion

in a

xilla

rylym

ph n

ode,

pne

umon

ia s

eque

lae,

ben

ign

mul

tinod

ular

goi

ter,

anat

omica

l misi

dent

ificat

ion

• PE

T ha

d no

false

pos

itive

FDG

upt

ake

in a

dren

al g

land

s•

PET

corre

ctly

chan

ged

M s

tage

, as

dete

rmine

d by

CI,

in 15

cas

es(1

4%)

Chan

ges

in th

erap

eutic

stra

tegy

• PE

T m

odifie

d th

erap

y in

27

patie

nts

(20%

) (1

0 to

cur

ative

sur

gery

, 8to

a m

ore

cura

tive

appr

oach

with

che

mo-

and

/or r

adia

tion

ther

apy,

9to

mor

e pa

lliativ

e ap

proa

ch)

• no

pat

ient

follo

w up

dat

a re

porte

d

Oth

er fi

ndin

gs•

auth

ors

foun

d PE

T m

ore

usef

ul th

an C

I in

eval

uatin

g ad

rena

l mas

ses

• fa

lse p

ositiv

e PE

T in

axilla

ry s

ite p

roba

bly c

ause

d by

extr

avas

ation

of

ante

cubi

tal v

ein

durin

g FD

G in

ject

ion

• lac

k of

ana

tom

ical m

arke

rs lim

ited

prec

ise lo

caliz

ation

of s

ome

PET

findin

gs•

CI +

PET

cou

ld in

crea

se th

e ac

cura

cy o

f det

ectio

n•

pros

pect

ive c

ompa

rison

nee

ded

to c

ompa

re P

ET w

ith b

one

scan

ning

Patie

nts/

Met

hods

Purp

ose

to p

rosp

ectiv

ely

com

pare

the

accu

racy

of F

DG-P

ET a

nd c

onve

ntio

nal im

agin

g (C

I) fo

r sta

ging

NSCL

C

Case

s14

1 co

nsec

utive

pat

ient

s be

twee

n 9/

94-1

0/96

with

new

ly di

agno

sed

NSCL

C ba

sed

onsp

utum

cyt

olog

y, n

eedl

e bi

opsy

, or f

lexib

le b

ronc

hosc

opy:

• ex

clusio

n cr

iteria

inclu

ded

poor

phy

siolo

gica

l sta

tus

(n=2

1) a

nd in

appr

opria

te fo

llow

up(n

=11)

• of

whi

ch 1

09 w

ere

enro

lled

in th

e st

udy:

• 77

men

, 32

wom

en; m

ean

age=

64 (4

4-83

)•

squa

mou

s ce

ll=50

; ade

nosq

uam

ous

cell=

8; a

deno

carc

inom

a=46

; und

iffere

ntia

ted

larg

ece

ll=5

• st

age

I=32

; sta

ge II

=8; s

tage

IIIA

=22;

stag

e III

B=8;

stag

e IV

=39;

N0=

32; N

1=20

; N2=

10;

N3=4

; T4=

4•

beni

gn c

ondi

tions

= n

onsp

ecific

infla

mm

atio

n, p

neum

onia

, mul

tinod

ular

goi

ter,

loca

lized

FDG

upt

ake

in h

epat

ic-sp

leni

c an

gle

of c

olon

• 66

cas

es w

ith s

uspe

cted

med

iast

inal

invo

lvem

ent o

n CT

or P

ET h

ad b

iops

y co

nfirm

atio

n

Met

hods

• all

pat

ients

had

CI b

efor

e PE

T; C

I= c

hest

and

abdo

mina

l CT

scan

ning

and

bone

scin

tigra

phy

• su

spici

ous

lesion

s on

bon

e sc

intigr

aphy

con

firm

ed b

y bo

ne ra

diogr

aphy

• co

ntra

st C

T po

sitive

crit

eria

> 1

0mm

on

shor

t axis

• PE

T da

ta a

nalyz

ed b

y vis

ual in

terp

reta

tion;

pos

itive

resu

lts=m

oder

ate

(abo

ut tw

ice th

eac

tivity

in c

ontra

late

ral o

r ref

eren

ce re

gion

) and

inte

nse

(mar

kedl

y hi

gher

than

refe

renc

eac

tivity

) FDG

upt

ake

• PE

T an

d CI

inte

rpre

ted

sepa

rate

ly by

2 n

uclea

r med

icine

read

ers

and

2 ra

diolog

y re

ader

sbl

inde

d to

N a

nd M

hist

olog

y bu

t not

blin

ded

to h

istol

ogy

of p

rimar

y tu

mor

• co

nfirm

atio

n of

sus

pect

ed m

edia

stin

al in

volve

men

t or d

istan

t met

asta

ses

on C

I or P

ETdo

ne w

ithin

21

days

of i

mag

ing

• N

stag

ing

conf

irmed

by

exte

nsive

nod

al s

ampl

ing

• M

sta

ging

conf

irmed

by

biops

y (2

1)or

clin

ical a

nd/o

r rad

iolog

ic fo

llow-

up (8

8); a

bsen

ce o

fde

mon

stra

ted

met

asta

ses

6 m

onth

s af

ter n

egat

ive im

agin

g co

nsid

ered

neg

ative

for

met

asta

ses

• sta

tistic

al an

alysis

by

patie

nt

Lim

itatio

ns o

f stu

dy d

esig

n•

choic

e of

N s

tage

coh

ort i

nflue

nced

by

imag

ing te

sts; o

nly b

iopsy

ver

ified

case

s inc

luded

in N

coh

ort (

work

up

bias

min

imize

d by

all p

atie

nts

havin

g bo

th te

sts)

• re

ader

s no

t blin

ded

to p

rimar

y tu

mor

hist

olog

y (p

artia

l tes

t rev

iew

bias

)•

stron

g as

socia

tion

betw

een

test

resu

lts a

nd d

eter

mina

tion

of g

old s

tand

ard

(diag

nosti

cre

view

bias

min

imize

d by

ext

ensiv

e no

dal s

ampl

ing

in N

sta

ging

• inc

omple

te re

porti

ng o

f met

hods

for e

valua

ting

chan

ges

in tre

atm

ent s

trate

gy

Dia

gn

ost

ic A

ccu

racy

Eff

icac

y o

f F

DG

PE

T in

Lu

ng

Can

cer

Stud

y

Bury

et a

l. (1

997)

(CHU

Liè

ge, B

elgi

um)

December 1998


Resu

lts/C

omm

ents

Defin

ing

adre

nal d

isea

se (2

3 m

alig

nant

lesi

ons,

10

beni

gn le

sion

s)PE

T vis

ual a

nalys

is: S

e=10

0%; S

p=80

%SU

R an

alys

is: m

alig

nant

lesio

ns m

ean=

6.28

± 2

.5 v

s. be

nign

lesion

sm

ean=

1.77

± 0

.89

(p <

0.0

001)

O

ther

find

ings

• Ch

arac

teris

tics

of m

alig

nant

mas

ses:

- m

ean

diam

eter

= 4

cm

- n=

6 ne

w on

follo

w up

CT

(mea

n tim

e=4

mon

ths)

, n=1

0 gr

owth

chan

ges

on C

T; n

=7 b

y bio

psy

- ch

ange

s in

adr

enal

mas

ses

on C

T co

nsist

ent w

ith c

hang

es in

thor

ax•

Char

acte

ristic

s of

ben

ign

mas

ses:

- n=

4 by

biop

sy; n

=5 w

ith fe

atur

es <

10

H on

CT;

n=1

with

ben

ignfe

atur

es o

n CT

Patie

nts/

Met

hods

Purp

ose

To a

sses

s PE

T in

diffe

rent

iatin

g be

nign

from

met

asta

tic a

dren

al m

asse

s in

pat

ient

s wi

thbr

onch

ogen

ic ca

rcin

oma

Ca

ses

27 c

onse

cutiv

e ca

ses

with

33

tota

l lesio

ns (2

3 m

alig

nant

, 10

beni

gn) p

rese

ntin

g to

thor

acic

surg

ery,

onco

logy,

or p

ulmon

ary

betw

een

Janu

ary

1993

and

Jan

uary

199

6 wi

th b

ronc

hoge

nicca

rcino

ma

and

an a

dren

al m

ass

dete

cted

by C

TCh

arac

teris

tics:

• 19

men

, 8 w

omen

; mea

n ag

e 57

yrs

(ran

ge 3

9-76

)•

24 w

ith N

SCLC

, 3 s

mal

l cel

l; bi

late

ral m

asse

s in

6 p

atie

nts

• m

ean

diam

eter

of a

dren

al m

asse

s=3

cm (r

ange

1-9

cm)

M

etho

ds•

FDG

PET

per

form

ed a

fter C

T•

Inde

pend

ent i

nter

pret

atio

n of

adr

enal

act

ivity

by

3 re

ader

s bl

inde

d to

clin

ical a

ndpa

thol

ogic

findi

ngs

and

othe

r im

agin

g te

st•

Posit

ive a

ctivi

ty=

activ

ity >

bac

kgro

und;

neg

ative

act

ivity

= ac

tivity

≤ b

ackg

roun

d•

ROI a

nd S

UR d

eter

mine

d bli

nded

to b

iopsy

resu

lts•

Conf

irmat

ion

of a

dren

al m

asse

s by

:-

perc

utan

eous

nee

dle b

iopsy

(n=1

1) w

ithin

a m

ean

of 5

day

s be

fore

PET

(n=9

) and

afte

r(n

=2),

- gr

owth

cha

racte

ristic

s on

follo

w up

(mea

n=4

mon

ths)

CT

(n=1

6), a

nd-

CT H

ouns

field

uni

t mea

sure

men

t < 1

0H d

iagn

ostic

of a

ben

ign

lesio

n (n

=6)

Li

mita

tions

of s

tudy

des

ign

• Hi

gh p

roba

bility

of m

alig

nanc

y a

nd b

enig

n co

nditio

ns n

ot d

epict

ed (p

oten

tial r

efer

ral b

ias)

• As

socia

tion

betw

een

PET

resu

lts a

nd c

hoice

of c

onfir

mat

ion

met

hod

uncle

ar (p

oten

tial

diag

nost

ic re

view

bias

)•

Incr

emen

tal v

alue

of P

ET in

test

seq

uenc

e no

t det

erm

ined

Stud

y

Eras

mus

et a

l. (1

997)

(Duk

e Un

iv. M

edica

l Cen

ter,

Durh

am, N

C)

December 1998


Resu

lts/C

omm

ents

Defin

ing

unkn

own

prim

ary

tum

or (3

2 m

alig

nant

cas

es, 1

4 be

nign

case

s)PE

T: S

e=94

%; S

p=86

%; a

ccur

acy=

91%

CT:

data

not

repo

rted

• PE

T fa

lse p

ositiv

es c

ause

d by

an

aspe

rgillo

ma

with

act

iveinf

lamm

ation

and

a fl

orid

absc

ess

• PE

T fa

lse n

egat

ives

caus

ed b

y a

1 cm

intra

pulm

onar

yad

enoc

arcin

oma

met

asta

sis a

nd b

ronc

hioa

lveol

ar c

arcin

oma

Med

iast

inal

/Hila

r inv

olve

men

t (w

ith 9

5% C

I) (2

0 po

sitiv

e ca

ses,

12

nega

tive

case

s)PE

T: S

e=80

% (5

6%-9

4%);

Sp=1

00%

(73%

-100

%);

accu

racy

=87%

(71%

-96%

)•

PET

accu

racy

(# p

atie

nts)

: N0=

12/1

2; N

1=3/

5; N

2=9/

11; N

3=4/

4CT

: Se=

50%

(27%

-73%

); Sp

=75%

(43%

-95%

); ac

cura

cy=5

9% (4

1%-

76%

) (p

<.02

for o

vera

ll acc

urac

y)•

CT a

ccur

acy

(# p

atie

nts)

: N0=

9/12

; N1=

2/5;

N2=

6/11

; N3=

2/4

• CT

false

pos

itive

node

s ca

used

by

nons

pecif

ic in

flam

mat

ion

inclu

ding

sarc

oidos

is, in

flam

mat

ory

pseu

dotu

mor

, and

pne

umon

ia•

PET

false

pos

itive

hila

r nod

es c

ause

d by

non

spec

ific in

flam

mat

ion

• PE

T dif

fere

ntiat

ed N

1/N2

dise

ase

from

N3

disea

se in

4 p

atien

ts, b

uton

ly 2

of 4

with

CT

Oth

er fi

ndin

gs•

cura

tive

rese

ctio

n wo

uld

have

bee

n av

oide

d in

2 p

atie

nts

with

N3

disea

se o

n PE

T bu

t not

with

CT

• tu

mor

invo

lvem

ent o

f per

ibron

chial

hila

r nod

es a

nd m

edias

tinal

node

sad

jace

nt to

the

bron

chus

may

be

enha

nced

with

ana

tom

etab

olic

imag

ing

• PE

T +

CT m

ay d

ecre

ase

the

need

for i

nvas

ive d

iagno

stic

proc

edur

essu

ch a

s m

edia

stin

osco

py

Patie

nts/

Met

hods

Purp

ose

to e

valua

te re

trosp

ectiv

ely th

e ac

cura

cy o

f FDG

PET

in th

orac

ic lym

ph n

ode

stagin

g in

patie

nts w

ith N

SCLC

Case

s46

con

secu

tive

patie

nts

(32

case

s, 1

4 be

nign

pro

cess

es) w

ho u

nder

went

thor

acot

omy

for

lung

tum

ors

from

199

4 to

8/9

5:•

41 m

en, 5

wom

en; m

ean

age=

56.7

yrs

(24-

78)

• sq

uam

ous

cell (

n=19

); ad

enoc

arcin

oma

(n=7

); la

rge

cell (

n=6)

• T1

=3; T

2=12

; T3=

10; T

4=7;

N0=

12; N

1=5;

N2=

11; N

3=4

• be

nign

con

ditio

ns:

pneu

mon

ia (n

=4);

tube

rcul

osis

(n=3

); on

e ea

ch o

f flo

rid a

bsce

ss,

aspe

rgillo

ma,

ham

arto

ma,

ane

urys

m o

f sub

clavia

n ar

tery

, lun

g fib

rosis

, inf

lam

mat

ory

pseu

dotu

mor

of w

hich

32

mal

igna

nt c

ases

und

erwe

nt fu

rther

med

iast

inal

eva

luat

ion

Met

hods

• all

pat

ients

unde

rwen

t con

trast

CT o

f che

st pr

ior to

PET

3 w

eeks

bef

ore

surg

ery

• po

sitive

nod

e on

CT

defin

ed a

s >

10m

m in

sho

rt ax

is di

amet

er•

blind

, ind

epen

dent

inte

rpre

tatio

n of

CT

by tw

o ex

perie

nced

radio

logist

s to

clin

ical a

nd P

ETfin

dings

• bl

ind,

inde

pend

ent v

isual

inte

rpre

tatio

n of

PET

by

2 ex

perie

nced

nuc

lear

med

icine

phys

ician

s•

hist

opat

holo

gy a

nd T

N cla

ssific

atio

n co

nfirm

ed s

urgi

cally

on

patie

nts

with

prim

ary

lung

canc

er•

surg

eon

cond

ucte

d th

orou

gh d

issec

tion

of m

edia

stin

al n

odes

, dat

a on

ext

ent n

ot re

porte

d•

PET

and

CT re

sults

map

ped

and

com

pare

d to

hist

olog

ic fin

ding

s•

statis

tical

analy

sis re

porte

d by

pat

ient

Lim

itatio

ns o

f stu

dy d

esig

n•

retro

spec

tive

stud

y of

sur

gica

l ser

ies—

high

pro

babi

lity o

f mal

igna

ncy

(pot

entia

l ref

erra

lbi

as)

• sm

all s

ampl

e siz

e lim

its s

ubgr

oup

anal

yses

• on

ly bi

opsy

ver

ified

case

s an

alyz

ed (w

ork-

up b

ias)

• as

socia

tion

betw

een

test

resu

lts a

nd b

iops

y co

nfirm

atio

n un

clear

(pot

entia

l dia

gnos

ticre

view

bias

, min

imize

d by

ext

ensiv

e no

dal s

ampl

ing)

Stud

y

Guh

lman

et a

l. (1

997)

(Uni

vers

ity o

f Ulm

, Ger

man

y)

December 1998


Resu

lts/C

omm

ents

Defin

ing

unkn

own

prim

ary

tum

or (4

4 po

sitiv

e no

des,

10

nega

tive

node

s)PE

T: S

e=93

%; S

p=70

%CT

: no

dat

a re

porte

d•

all f

alse

pos

itives

cau

sed

by g

ranu

lom

as•

3 fa

lse n

egat

ives

cau

sed

by p

oor q

uality

PET

sca

ns (h

yper

glyc

emia

at th

e tim

e of

sca

n, n

o at

tenu

atio

n co

rrect

ion,

r ou

tdat

ed s

cann

er);

one

false

neg

ative

due

to re

nal c

ell c

arcin

oma

unex

plai

ned

Med

iast

inal

invo

lvem

ent—

N2 d

isea

se o

nly

(9 p

ositi

ve n

odes

, 9ne

gativ

e no

des)

PET:

Se=

67%

; Sp=

100

%CT

: Se

=56%

; Sp=

100%

• sm

all n

umbe

rs, s

elec

tion

and

verif

icatio

n bi

as m

ay c

ontri

bute

to la

ckof

sig

nific

ance

bet

ween

PET

and

CT

Oth

er fi

ndin

gs/C

omm

ents

• qu

antita

tive

analy

sis m

ay a

llow

mor

e ac

cura

te d

iffere

ntiat

ion o

fdi

seas

e•

bala

nced

disc

ussio

n of

the

influ

ence

of s

tudy

size

, sel

ectio

n bi

as a

ndve

rifica

tion

bias

es o

n re

sults

• fu

rther

stu

dy n

eede

d to

clar

ify ro

le of

PET

in s

tagin

g•

cost

-effe

ctive

ness

stu

dies

nee

ded

prio

r to

advo

catin

g th

e ro

utin

e us

eof

PET

in m

anag

emen

t of N

SCLS

Patie

nts/

Met

hods

Purp

ose

• to

eva

luat

e re

trosp

ectiv

ely

PET

in c

hara

cter

izing

pul

mon

ary

nodu

les

and

stag

ing

bron

chog

enic

carc

inom

a•

to c

ompa

re C

T wi

th P

ET fo

r dia

gnos

ing

N2 d

iseas

e

Case

s49

con

secu

tive

patie

nts

pres

entin

g be

twee

n 9/

94 a

nd 3

/96

(31

mali

gnan

t cas

es, 1

8 be

nign

case

s) w

ith 5

4 pu

lmon

ary

nodu

les (4

4 po

sitive

nod

ules,

10 n

egat

ive n

odule

s):

• 45

men

, 4 w

omen

; mea

n ag

e=63

(37-

85)

• sq

uam

ous=

15 n

odul

es; a

deno

carc

inom

a=16

; lar

gece

ll=3;

aden

osqu

amou

s=3;

bron

choa

lveol

ar=2

; aty

pica

l car

cinoi

d=1;

sm

all c

ell=

1; re

nal

cell=

2;m

alig

nant

mel

anom

a=1

• be

nign

con

ditio

ns: g

ranu

lom

a=4;

ham

arto

ma=

3; n

ecro

tic ti

ssue

=2; f

unga

l bal

l=1

• ex

clusio

n cr

iteria

: in

dete

rmin

ate

PET

scan

(2) a

nd in

adeq

uate

hist

opat

holo

gic

info

rmat

ion

of m

edia

stin

um (1

1)•

18 o

f 31

mali

gnan

t cas

es h

ad c

omple

te P

ET, C

T, a

nd h

istop

atho

logy

infor

mat

ion a

ndwe

re in

clude

d in

analy

sis o

f med

iastin

al no

des

(N2

only)

Met

hods

• CT

per

form

ed a

nd in

terp

rete

d pr

ior to

PET

• CT

inte

rpre

ted

by o

ne in

vest

igat

or; p

ositiv

e m

edia

stin

al ly

mph

nod

es >

1 c

m in

sho

rt ax

isdi

amet

er•

initia

l PET

sca

ns v

isual

ly in

terp

rete

d by

one

inve

stig

ator

not

blin

ded

to C

XR o

r CT

findin

gs•

blin

ded

med

iast

inal

PET

imag

es re

read

by

two

inve

stig

ator

s•

PET

FDG

upt

ake

class

ified

as p

ositiv

e, n

egat

ive o

r ind

eter

min

ate—

no d

iffere

nce

betw

een

initia

l rea

d an

d re

read

, but

met

hods

for c

ompa

rison

not

des

crib

ed•

all p

ulmon

ary

nodu

les c

onfir

med

by

histo

- or c

ytopa

tholo

gy; e

xtent

of n

odal

sam

pling

not

repo

rted

• da

ta a

nalyz

ed b

y no

de

Lim

itatio

ns o

f stu

dy d

esig

n•

smal

l num

ber o

f sub

ject

s•

retro

spec

tive

desig

n--p

atie

nt s

ourc

e an

d filt

ers

uncle

ar (p

oten

tial r

efer

ral b

ias)

• in

fluen

ce o

f im

agin

g te

sts

on s

elec

tion

of s

urgi

cal c

andi

date

s un

clear

; N s

tage

coh

ort

rest

ricte

d to

bio

psy

verif

ied

case

s (w

ork

up b

ias)

• as

socia

tion

of te

st re

sults

and

det

erm

inat

ion

of g

old

stan

dard

unc

lear

(pot

entia

l dia

gnos

ticre

view

bias

)•

inte

rpre

tatio

n of

prim

ary

tum

or n

ot b

linde

d (te

st re

view

bias

)

Stud

y

Hagb

erg

et a

l. (1

997)

(VA

Palo

Alto

Hea

lth C

are

Syste

man

d St

anfo

rd U

nive

rsity

Sch

ool o

fM

edici

ne)

December 1998


Resu

lts/C

omm

ents

Dete

ctin

g m

edia

stin

al ly

mph

nod

e m

etas

tase

s (2

8 po

sitiv

e no

des,

84 n

egat

ive

node

s)PE

T: S

e=89

%*;

Sp=9

9%; P

PV=

96%

; NPV

=97%

; acc

urac

y=97

%CT

: Se=

57%

*; Sp

=94%

; PPV

=76%

; NPV

=87%

; acc

urac

y=85

%*

(P=.

0066

)

(n=4

7 pa

tient

s)•

PET:

45/

47 (9

6%) c

orre

ctly

stage

d vs

. CT:

37/

47 (7

9%) (

P=.0

1341

)

Oth

er fi

ndin

gs•

no s

tatis

tical

ly sig

nific

ant d

iffer

ence

bet

ween

sta

ging

with

conv

entio

nal C

T an

d wi

th s

pira

l CT

• co

rrela

tion

of n

odal

sta

tion

on im

agin

g wi

th s

urgi

cal r

esul

ts m

atch

edex

cept

for o

ne c

ase

Patie

nts/

Met

hods

Purp

ose

to c

ompa

re p

rosp

ectiv

ely

(??)

the

accu

racy

of F

DG P

ET w

ith C

T in

sta

ging

NSC

LC

Case

s62

sur

gical

cand

idate

s wi

th s

uspe

cted

or p

rove

n NS

CLC

who

had

PET

betw

een

2/94

and

3/96

and

who

had

no

prior

neo

adjuv

ant t

hera

py o

r diab

etes

• ex

clusio

n cr

iteria

: in

adeq

uate

CT=

2; d

istan

t met

asta

ses=

8; in

adeq

uate

nod

al s

ampl

ing=

5•

ther

efor

e, 4

7 pa

tient

s wi

th s

uspe

cted

or c

onfir

med

NSC

LC o

f mixe

d ty

pes

rem

aine

d in

the

study

• sq

uam

ous=

24; a

deno

carc

inom

a=17

; lar

ge c

ell=

6•

29 (6

2%) w

ith n

odal

met

asta

ses;

N0-

N1=3

4; N

2=7;

N3=

6

Met

hods

• CT

, em

issio

n an

d tra

nsm

issio

n PE

T ob

tain

ed o

n al

l pat

ient

s•

blin

d, in

depe

nden

t int

erpr

etat

ion

of P

ET a

nd C

T sc

ans

befo

re s

urgi

cal s

tagi

ng•

CT p

ositiv

e cr

iteria

=nod

es >

10m

m in

sho

rt ax

is dia

met

er, e

xcep

t upp

er p

arat

rach

eal

statio

ns >

7m

m o

r inf

raca

rinal

statio

n >

11m

m•

pres

ence

and

site

of m

edia

stin

al a

nd tr

ache

obro

nchi

al n

odes

reco

rded

acc

ordi

ng to

ATS

lymph

nod

e st

atio

n m

appi

ng s

yste

m; e

xten

t of l

ymph

nod

e m

etas

tase

s cla

ssifie

d ac

cord

ing

to A

JC lu

ng c

ance

r sta

ging

sys

tem

• all

pat

ients

unde

rwen

t exte

nded

sur

gical

lymph

nod

e sta

ging

rega

rdles

s of

PET

or C

Tfin

ding

s or

nod

al s

ize•

PET

and

CT a

vaila

ble

to s

urge

on d

urin

g su

rger

y•

patie

nts

unde

rgoi

ng le

ft th

orac

otom

y ha

d lim

ited

sam

plin

g of

med

iast

inal

lym

ph n

odes

; car

ewa

s ta

ken

to re

sect

all p

reop

erat

ively

stag

ed p

ositiv

e lym

ph n

odes

• PE

T an

d CT

cor

rela

ted

with

hist

opat

holo

gic

resu

lts

Lim

itatio

ns o

f stu

dy d

esig

n•

Real

-tim

e pr

ospe

ctive

des

ign

uncle

ar•

Patie

nt s

ourc

e un

clear

and

hig

h pr

obab

ility

of m

alig

nanc

y in

sur

gica

l ser

ies

(pot

entia

lre

ferra

l bia

s)•

Onl

y bi

opsy

ver

ified

case

s an

alyz

ed (w

ork

up b

ias)

• St

rong

cor

relat

ion b

etwe

en im

aging

resu

lts a

nd b

iopsy

con

firm

ation

(diag

nosti

c re

view

bias

) min

imize

d by

nod

al s

ampl

ing

Stud

y

Stei

nert

et a

l. (1

997)

(Uni

vers

ity H

ospi

tal,

Zuric

h,Sw

itzer

land

)

December 1998


Resu

lts/C

omm

ents

Dete

ctin

g m

edia

stin

al in

volv

emen

t (15

pos

itive

cas

es, 3

5 ne

gativ

eca

ses)

PET:

Se=

67%

; Sp=

97%

; acc

urac

y=88

%; P

PV=9

1%; N

PV=8

7%CT

: Se

=67%

; Sp=

63%

; acc

urac

y=64

%; P

PV=4

3%; N

PV=8

1%PE

T +

CT:

Se=

93%

; Sp=

97%

; acc

urac

y=96

%; P

PV=9

3%; N

PV=9

7%•

of 1

8 dis

cord

ant r

esult

s, CT

was

cor

rect

in 1/

18, a

nd P

ET w

as c

orre

ctin

17/

18 (p

=0.0

04)

Auth

ors’

com

men

ts•

med

iast

inos

copy

cou

ld b

e om

itted

in p

atie

nts

with

nor

mal

CT

and

PET

or in

pat

ients

with

abn

orm

al CT

but

nor

mal

PET

• al

l pat

ient

s wi

th a

bnor

mal

med

iast

inal

PET

sho

uld

still

proc

eed

toin

vasiv

e m

edia

stin

al s

tagi

ng, t

o be

sur

e th

at n

o pa

tient

with

N0

or N

1di

seas

e is

deni

ed th

e ch

ance

of c

ure

by d

irect

sur

gica

l res

ectio

n•

in th

is st

udy

the

need

for i

nvas

ive m

edia

stin

al s

tagi

ng c

ould

be

redu

ced

to 1

3 or

50

patie

nts,

resu

lting

in im

porta

nt s

aving

s in

oper

atio

n tim

e•

if ac

cura

cy o

f med

iast

inal

PET

will

be c

onfir

med

in fu

ture

dat

a, it

islik

ely

that

PET

will

subs

tant

ially

cha

nge

curre

nt c

linica

l pra

ctice

of

stagin

g of

NSC

LC

Patie

nts/

Met

hods

Purp

ose

to c

ompa

re p

rosp

ectiv

ely??

CT,

PET

, and

PET

+ C

T in

stagin

g m

edias

tinal

lymph

nod

es in

patie

nts w

ith N

SCLS

Case

sUn

know

n #

of p

atie

nts

with

sus

pect

ed o

r bio

psy

prov

en N

SCLC

who

wer

e po

tent

ially

oper

able

afte

r sta

ndar

d st

agin

g fo

r dist

ant m

etas

tase

s•

exclu

sion

crite

ria:

diab

etes

; tre

atm

ent w

ith o

ral c

ortic

oste

roid

s; is

chem

ic ca

rdio

myo

path

y;m

edias

tinal

invas

ion o

f prim

ary

tum

or; o

bviou

s bu

lky m

etas

tase

s•

reco

rds

of 5

0 pa

tient

s tre

ated

bet

ween

9/9

5 an

d 4/

96 w

ere

anal

yzed

- sq

uam

ous=

32; a

deno

carc

inom

a=10

; lar

ge c

ell=

8-

T1==

3;T2

=32;

T3=

15; N

0=35

; N2=

15

Met

hods

• in

terp

reta

tion

of c

ontra

st C

T by

two

inte

rpre

ters

blin

ded

to b

ronc

hosc

opic

or p

atho

logi

cfin

ding

s; p

ositiv

e no

de ≥

15

mm

long

axis

dia

met

er•

SUV

PET

imag

es in

terp

rete

d bli

nded

to c

linica

l, CT

, and

pat

holog

ic da

ta b

y tw

oin

depe

nden

t rea

ders

; five

poi

nt s

emiq

uant

itativ

e sc

ale

used

1-5

; pos

itive

node

= 4

or 5

• CT

+ P

ET v

isual

ly in

terp

rete

d by

two

read

ers

blin

ded

to p

atho

logi

c da

ta•

surg

ical s

tagi

ng d

one

by m

edia

stin

osco

py a

nd in

traop

erat

ive s

tagi

ng in

cas

e of

rese

ctio

n•

CT, P

ET, a

nd s

urgi

cal s

tagi

ng c

arrie

d ou

t with

in o

ne m

onth

• M

LN m

ap u

sed

for i

mag

ing

and

surg

ical s

tagi

ng•

data

ana

lyzed

by

patie

nt

Lim

itatio

ns o

f stu

dy d

esig

n•

Smal

l sam

ple

size

• Li

mite

d pa

tient

dat

a; h

igh

prob

abilit

y of

mal

igna

ncy

(pot

entia

l ref

erra

l bia

s)•

pros

pect

ive d

esig

n un

clear

• on

ly bi

opsy

ver

ified

case

s an

alyz

ed (w

ork

up b

ias)

• as

socia

tion

betw

een

test

resu

lts a

nd d

eter

min

atio

n of

gol

d st

anda

rd u

ncle

ar (d

iagn

ostic

revie

w bi

as)

• ex

tent

of n

odal

sam

plin

g no

t rep

orte

d•

blin

ding

to c

linica

l dat

a on

visu

al in

terp

reta

tion

not r

epor

ted

(pot

entia

l tes

t rev

iew

bias

)•

met

hods

for a

sses

sing

chan

ges

in tr

eatm

ent n

ot re

porte

d

Stud

y

Vans

teen

kiste

et a

l. (1

997)

(UHG

, Leu

ven,

Bel

gium

)

December 1998


Resu

lts/C

omm

ents

Dete

ctio

n of

kno

wn

prim

ary

(29

lesi

ons)

PET

FDG

upt

ake:

9.1±

4.6

(TM

R±S

D)CT

: 43

.3±1

8.5m

m (m

ean

± SD

)

Med

iast

inal

lym

ph n

ode

met

asta

ses

(17

posi

tive

regi

ons,

54

nega

tive

regi

ons)

PET:

Se=

76%

; Sp=

98%

*; Ac

cura

cy=9

3%**

; PPV

=93%

; NPV

=93%

CT:

Se=6

5%; S

p=87

%*;

Accu

racy

=82%

**; P

PV=6

1%; N

PV=8

9%*,*

* (P<

0.05

)•

All P

ET fa

lse n

egat

ives

< 7m

m in

sho

rt ax

is di

amet

er d

ue to

par

tial

volu

me

effe

ct•

smal

lest

true

pos

itive

on P

ET w

as 7

mm

in s

hort

axis

diam

eter

• CT

false

pos

itives

cau

sed

by n

on-s

pecif

ic in

flam

mat

ory

chan

ges

and

an e

nlar

ged

trach

eobr

onch

ial ly

mph

nod

e of

unr

epor

ted

caus

e•

PET

false

pos

itive

caus

ed b

y an

enla

rged

trac

heob

ronc

hial ly

mph

node

of u

nrep

orte

d ca

use

Auth

ors’

Com

men

ts•

volu

ntar

y an

d in

volu

ntar

y m

ovem

ent c

an c

ontri

bute

toun

dere

stim

atio

n of

FDG

upt

ake

• m

edias

tinal

evalu

ation

may

hav

e be

en lim

ited

by P

ET fi

eld o

f view

• us

e of

qua

ntita

tive

anal

ysis

usin

g PE

T is

limite

d in

lym

ph n

ode

eval

uatio

n du

e its

com

plex

ity, t

he in

fluen

ce o

f the

par

tial v

olum

eef

fect,

and

limite

d vis

ual id

entifi

catio

n of

lym

ph n

odes

• au

thor

s su

gges

t PET

as

a co

mpl

emen

tary

dia

gnos

tic m

etho

d wi

thCT

; im

prov

emen

ts in

tech

nica

l and

qua

ntita

tive

met

hods

sho

uld

impr

ove

the

diag

nost

ic ab

ility

of P

ET

Patie

nts/

Met

hods

Purp

ose

to c

ompa

re ?

pros

pect

ively

FDG

PET

with

CT

in th

e de

tect

ion

of m

edia

stin

al ly

mph

nod

em

etas

tase

s

Case

s29

new

ly di

agno

sed

patie

nts

with

NSC

LC o

f mixe

d ty

pes

who

had

unde

rgon

e su

rger

y an

dwh

o ha

d pa

thol

ogic

conf

irmat

ion

of d

iseas

e•

aden

ocar

cinom

a=18

; squ

amou

s=9;

ade

nosq

uam

ous=

1; la

rge

cell=

1•

N0-N

1=17

; N2=

11; N

3=1

• 13

2 ou

t of 2

61 m

edias

tinal

lymph

nod

es w

ere

surg

ically

rese

cted

and

histo

path

ology

conf

irmed

of

- 71

regi

ons

had

CT, P

ET, a

nd h

istop

atho

logi

c in

form

atio

n an

d we

re in

clude

d in

the

stud

y

Met

hods

• m

edias

tinal

lymph

nod

es c

lassif

ied in

to n

ine re

gions

bas

ed o

n m

appin

g pr

opos

ed b

y th

eJa

pan

Lung

Can

cer S

ocie

ty•

FDG

upt

ake

mea

sure

d by

TM

R of

the

prim

ary

tum

or•

visua

l inte

rpre

tatio

n of

PET

imag

es p

erfo

rmed

by

3 nu

clear

med

icine

read

ers

• PE

T po

sitive

crit

eria

wer

e FD

G u

ptak

e in

nod

es>

that

in o

ther

med

iast

inal

stru

ctur

es•

cont

rast

CT

inte

rpre

ted

by 2

radi

olog

ists

• CT

pos

itive

node

s ≥1

0 m

m o

n sh

ort a

xis d

iam

eter

• go

ld s

tand

ard

biop

sy o

btai

ned

surg

ically

• da

ta a

nalyz

ed b

y no

dal r

egio

n

Lim

itatio

ns o

f stu

dy d

esig

n•

not r

eal-t

ime

pros

pect

ive d

esig

n (re

ferra

l bia

s)•

regio

ns in

clude

d in

analy

sis re

pres

ent a

n un

know

n nu

mbe

r of p

atien

ts•

only

biop

sy v

erifie

d ca

ses

anal

yzed

(wor

k up

bia

s)•

blin

ding

of r

eade

rs n

ot re

porte

d (te

st re

view

bias

)•

asso

ciatio

n be

twee

n te

st re

sults

and

det

erm

inat

ion

of g

old

stan

dard

unc

lear

, and

ext

ent

of n

odal

sam

plin

g no

t des

crib

ed (p

oten

tial d

iagn

ostic

revie

w bi

as)

Stud

y

Sasa

ki et

al.

(199

6)(K

yush

u Un

ivers

ity, F

ukuo

ka,

Japa

n)

December 1998


Resu

lts/C

omm

ents

Diag

nost

ic A

ccur

acy

(37

mal

igna

ncie

s, 1

5 be

nign

)O

vera

llPE

T+CT

: Se

=95%

; Sp=

87%

; acc

urac

y=92

%no

dule

s ≤

1.5

cmPE

T+CT

: Se

=83%

; Sp=

100%

nodu

les >

1.5

cmPE

T+CT

: Se

=100

%; S

p=67

%

• 2

false

pos

itives

due

to h

istop

lasm

a gr

anul

oma

with

act

ive in

flam

mat

ion

• 2

false

neg

ative

s we

re 1

cm

sca

r ade

noca

rcin

oma

and

aden

ocar

cinom

a

Diag

nost

ic T

hink

ing

Effic

acy

Baye

s’ T

heor

em•

LR fo

r mal

igna

nt S

PN w

ith a

bnor

mal

PET

=7.1

1 (9

5% C

I, 6.

36 to

7.9

6)•

LR fo

r mal

igna

nt S

PN w

ith n

orm

al P

ET=0

.06

(95%

CI,

0.05

to 0

.07)

ROC

curv

e an

alys

isPE

T alo

ne w

as th

e be

st pr

edict

or o

f mali

gnan

cy a

t diffe

rent

leve

ls of

pCA

,th

e st

anda

rd c

riter

ia th

e wo

rst,

and

stan

dard

crit

eria

+ P

ET w

asin

term

edia

te

Patie

nts/

Met

hods

Purp

ose

to c

ompa

re th

e pr

obab

ility

of c

ance

r (pC

A) in

a S

PN u

sing

stand

ard

crite

ria w

ith B

ayes

ian A

nalys

is an

dPE

T (re

trosp

ectiv

e an

alysis

)

Case

s52

con

secu

tive

patie

nts

(37

mal

igna

nt c

ases

, 15

beni

gn c

ases

) who

met

the

follo

wing

sel

ectio

n cr

iteria

:•

unde

rwen

t PET

imag

ing b

etwe

en A

pril 1

990

and

Febr

uary

199

4•

nonc

alcif

ied,

non

cavit

ary

SPN

base

d on

CXR

and

CT

class

ified

as in

dete

rmin

ate

• ag

e >

30 y

ears

• no

dule

size

≤ 3

cm

• gr

oup

includ

ed 3

pat

ients

with

extr

atho

racic

mali

gnan

cy a

nd o

ne p

atien

t with

sta

ble n

odule

for >

2 y

rsRe

porte

d pa

tient

cha

ract

erist

ics:

• 43

men

, 9 w

omen

; mea

n ag

e=63

.6 y

rs ±

11.

3yrs

; 79%

cur

rent

sm

oker

s of

whi

ch 5

2% s

mok

ed ≥

20

cigs/d

ay•

Edge

cha

racte

ristic

s (%

mali

gnan

t cas

es v

s. %

ben

ign c

ases

): S

harp

, sm

ooth

=14%

vs.2

0%;

Lobu

late

d=30

% v

s. 4

0%; S

light

ly irr

egul

ar w

/ few

spi

cula

tions

=38%

vs.

33%

; Gro

ssly

irreg

ular

and

spicu

late

d=19

% v

s. 7

%

Met

hods

• PE

T pe

rform

ed w

ithin

2-4

wee

ks a

fter C

T; C

T de

nsito

met

ry n

ot p

erfo

rmed

• hi

stol

ogic

diag

nosis

obt

aine

d by

thor

acot

omy,

med

iast

inos

copy

, bro

ncho

scop

y, o

r nee

dle

lung

bio

psy

• qu

alita

tive

PET

scan

s re

ad b

y on

e re

ader

blin

ded

to h

istol

ogy;

clin

ical a

nd ra

diol

ogic

data

ava

ilabl

e to

the

read

er v

aried

, but

size

and

loca

tion

was

know

n in

all p

atien

ts•

beni

gn P

ET=n

o fo

cal F

DG u

ptak

e; m

alig

nant

PET

=foc

al F

DG a

ccum

ulat

ion

grea

ter t

han

surro

undi

ngtis

sue

but m

ore

than

mild

• no

dule

edg

e on

CT

inte

rpre

ted

inde

pend

ently

by

2 pu

lmon

olog

ists

usin

g 4

type

cla

ssific

atio

n sy

stem

blind

ed to

clin

ical d

iagno

sis; d

iscre

pant

inte

rpre

tatio

ns re

ache

d by

con

sens

us•

odds

-likel

ihoo

d of

mal

igna

ncy

estim

ated

usin

g Ba

yes

Theo

rem

• st

anda

rd c

riter

ia fo

r pro

babi

lity o

f can

cer (

pCA)

bas

ed o

n pa

tient

’s ag

e, s

mok

ing

hist

ory,

hist

ory

of p

rior

mal

igna

ncy,

nod

ule

size

and

edge

, and

pre

senc

e of

cal

cifica

tion

• pC

A of

sta

ndar

d cr

iteria

com

pare

d to

sta

ndar

d cr

iteria

+ P

ET a

nd P

ET a

lone

Lim

itatio

ns o

f Stu

dy D

esig

n•

retro

spec

tive

desig

n•

all p

atien

ts ha

s inv

asive

biop

sy d

eter

mina

tion,

imply

ing a

high

inde

x of

sus

picion

for m

align

ancy

(refe

rral b

ias)

• so

urce

of p

atie

nt c

ohor

t inf

luen

ced

by te

st re

sults

(wor

k up

bia

s)•

asso

ciatio

n be

twee

n te

st re

sults

and

det

erm

inat

ion

of g

old

stan

dard

unc

lear

(pot

entia

l dia

gnos

tic re

view

bias

)•

blin

ding

of c

linica

l and

radi

olog

ic in

form

atio

n va

ried

(test

revie

w bi

as)

• PE

T an

d ot

her t

ests

not i

ndep

ende

nt, a

requ

irem

ent o

f Bay

es’ T

heor

em•

pre-

PET

prob

abilit

y of

can

cer i

n pa

tient

s un

know

n

Dia

gn

ost

ic A

ccu

racy

an

d D

iag

no

stic

Th

inki

ng

Eff

icac

y S

tud

ies

of

FD

G P

ET

in S

olit

ary

Pu

lmo

nar

y N

od

ule

s

Stud

y

Dewa

n et

al.

(199

7)(C

reig

hton

Uni

vers

ity a

ndVA

MC

Om

aha,

NE)

December 1998


Resu

lts/C

omm

ents

Defin

ing

SPN

(60

mal

igna

nt c

ases

, 29

beni

gn c

ases

) rep

orte

d w

ith 9

5% C

IO

vera

ll (≤

4cm

)SU

V: S

e=92

% (8

2-10

0%);

Sp=9

0% (7

9-10

0%);

Acc=

91%

; LR+

=9.0

; LR-

=0.0

9Vi

sual:

Se=

98%

(95-

100%

); Sp

=69%

(57-

81%

); Ac

c=89

%; L

R+=3

.0; L

R-=0

.02

• M

align

ant m

ean

SUV

± 1

SD=6

.9 ±

3.9

vs.

benig

n =1

.7 ±

1.0

(P <

0.0

01)

≤ 1.

5cm

(15

posit

ives,

19

nega

tives

)SU

V: S

e=80

% (6

0-10

0%);

Sp=9

5% (8

5-10

0%);

Acc=

88%

; LR+

=15.

0; L

R-=0

.2Vi

sual

: Se=

100%

(100

-100

%);

Sp=7

4% (5

5-93

%);

Acc=

85%

; LR+

=4.0

; LR-

=0.0

>1.5

cm (4

5 po

sitive

s, 1

0 ne

gativ

es)

SUV:

Se=

96%

(90-

100%

); Sp

=80%

(55-

100%

); Ac

c=93

%; L

R+=5

.0; L

R-=0

.06

Visu

al: S

e=98

% (9

4-10

0%);

Sp=6

0% (4

6-74

%);

Acc=

91%

; LR+

=2.0

; LR-

=0.0

4≤

3.0c

m (5

1 po

sitive

s, 2

6 ne

gativ

es)

SUV:

Se=

90%

(82-

98%

); Sp

=92%

(85-

99%

); Ac

c=91

%; L

R+=1

2.0;

LR-

=0.1

Visu

al: S

e=98

% (9

4-10

0%);

Sp=6

9% (5

6-82

%);

Acc=

88%

; LR+

=3.0

; LR-

=0.0

3

Oth

er fi

ndin

gs•

Κ=0

.95;

2/8

9 di

scre

pant

cas

es c

ause

d by

gra

nulo

ma

and

acut

e in

flam

mat

ion

• be

nign

con

ditio

ns:

gran

ulom

a (7

), co

ccid

iom

ycos

is (4

), be

nign

cel

lula

r deb

ris(4

), no

nspe

cific

infla

mm

atio

n (3

), ne

crot

izing

gra

nulo

ma

(3),

fibro

sis (1

),he

man

giom

a (1

), as

perg

illosis

(1),

met

apla

sia (1

)•

mal

igna

ncie

s: N

SCLC

(50)

, mel

anom

a (5

), Ho

dgkin

’s lym

phom

a (1

), sm

all-c

ell

(1),

mal

igna

nt n

eura

l tum

or (1

), m

alig

nant

car

cinoi

d (1

), co

lon

canc

er (1

)•

SUV

false

neg

ative

s (5

): 2

.0cm

bro

nchi

oalve

olar

can

cer,

1.5c

m s

quam

ous

cell

canc

er, 1

.0cm

mel

anom

a m

ets,

2.5

cm s

quam

ous

cell c

ance

r in

a pa

tient

with

bloo

d gl

ucos

e=34

1; a

ll fal

se n

egat

ives

in R

upp

er lo

be•

Visu

al fa

lse n

egat

ives

(1):

2.0c

m b

ronc

hioa

lveol

ar c

ance

r•

SUV

and

visua

l fals

e po

sitive

s (3

): g

ranu

loma,

nec

rotiz

ing g

ranu

loma,

necr

otizi

ng g

ranu

loma

with

hist

oplas

mos

is; 2

in R

upp

er lo

be, 1

in l

uppe

r lob

e•

Seru

m g

luco

se v

alue

s on

61

patie

nts,

mea

n ±

SD=9

9 ±

56 m

g/dL

; 2/7

diab

etics

had

elev

ated

glu

cose

leve

ls wi

th 1

false

pos

itive

and

2 fa

lse n

egat

ive re

sults

• In

4 c

ases

CXR

did

not i

dent

ify th

e SP

N

Auth

ors’

com

men

ts•

Resu

lts fr

om v

isual

ana

lysis

mig

ht b

e m

ore

help

ful t

han

quan

titativ

e an

alys

is fo

rsm

all n

odul

es (≤

1.5

cm) a

nd in

cas

es in

whic

h ele

vate

d glu

cose

leve

ls ar

eun

avoid

able

to re

duce

the

num

ber o

f fals

e ne

gativ

e ca

ses

• G

iven

the

mult

isite

nat

ure

of th

e stu

dy a

nd m

ultipl

e ra

diolog

ists

used

to in

terp

ret

the

films

acro

ss s

ites,

study

pop

ulatio

n is

repr

esen

tativ

e of

the

prop

ortio

n of

inde

term

inat

e SP

Ns fr

om th

e sit

es in

clude

d

Patie

nts/

Met

hods

Purp

ose

To p

rosp

ectiv

ely e

valua

te th

e dia

gnos

tic a

ccur

acy

of F

DG-P

ET im

aging

in e

valua

ting

SPNs

Case

s89

of 1

05 c

onse

cutiv

e pa

tient

s wh

o m

et th

e fo

llowi

ng in

clusio

n cr

iteria

:•

Imag

ing

perfo

rmed

bet

ween

Oct

ober

199

3 an

d Au

gust

199

4•

SPNs

0.7

cm-4

.0cm

in s

ize v

isual

ized

on C

T•

Cons

ider

ed in

dete

rmin

ate

for m

alig

nanc

y by

CXR

and

CT

and

clini

cal d

ata

• De

finitiv

e pa

thol

ogic

conf

irmat

ion

by T

TNA

(n=2

9) o

r sur

gery

(n=6

0)Ex

clude

d pa

tient

s:

8 no

def

initiv

e pa

thol

ogy;

4 d

efin

itely

beni

gn S

PN o

n CX

R/CT

; 2 w

/o C

TRe

porte

d pa

tient

cha

ract

erist

ics:

• 61

men

, 28

wom

en; m

ean

age=

63

± 9.

5 yr

s

Met

hods

• Im

agin

g pe

rform

ed p

rior t

o tre

atm

ent o

f SPN

• AP

and

late

ral C

XR a

nd C

T of

at l

east

ches

t and

adr

enals

obt

ained

; thin

-sec

tion

trans

axial

imag

es a

nd IV

con

trast

used

in s

ome

studie

s•

Inde

pend

ent q

ualita

tive

inte

rpre

tatio

n of

CXR

and

CT

by re

ader

s at

2 p

artic

ipat

ing

sites

oth

erth

an w

here

the

stud

ies

were

per

form

ed, b

linde

d to

clin

ical,

PET,

and

gol

d st

anda

rd re

sults

• Se

miqu

antita

tive

anal

ysis

(SUV

) per

form

ed; S

UV>

2.5

= m

alig

nant

• In

depe

nden

t visu

al an

alysis

of P

ET b

y 2

read

ers

(of 3

ava

ilable

read

ers)

blin

ded

to c

linica

l,CX

R/CT

, and

gold

sta

ndar

d re

sults

in e

ach

case

; foc

al up

take

> m

edias

tinal

blood

poo

lst

ruct

ures

= m

alig

nant

• PE

T co

mpa

red

to h

istol

ogy;

Se,

Sp,

acc

urac

y, a

nd L

Rs c

alcu

late

d•

Κ v

alue

ass

esse

d fo

r int

erob

serv

er v

aria

bility

Lim

itatio

ns o

f stu

dy d

esig

n•

smal

l sam

ple

size

in s

ubgr

oup

anal

yses

• ?

real

-tim

e pr

ospe

ctive

dat

a co

llect

ion

or r

etro

spec

tive

data

col

lect

ion

from

sur

gica

l ser

ies;

cond

itiona

l inde

pend

ence

am

ong

test

s un

clear

• hi

gh p

reva

lenc

e of

mal

igna

ncy

in s

tudy

pop

ulat

ion

(refe

rral b

ias)

• in

clusio

n cr

iterio

n of

bio

psy

verif

icatio

n bi

ased

towa

rd p

atie

nts

with

hig

h pr

obab

ility

of m

alig

nanc

y(w

ork-

up b

ias)

• bli

nding

of s

urge

ons

to P

ET re

sults

not

alw

ays

cond

ucte

d fo

r eth

ical r

easo

ns (d

iagno

stic

revie

wbi

as)

• pr

e-PE

T pr

obab

ility

of c

ance

r in

patie

nts

unkn

own

Note

: So

me

sites

(eg.

Cre

ight

on U

nive

rsity

Med

ical C

ente

r, O

mah

a, N

ebra

ska)

may

hav

e in

clude

dda

ta fr

om p

revio

usly

publ

ished

pat

ient

ser

ies,

whi

ch w

ere

revie

wed

in th

e 19

96 M

DRC

PET

asse

ssm

ent.

Stud

y

Lowe

et a

l. (1

998)

(mul

ti-sit

e st

udy

from

9U.

S. s

ites)

December 1998


Resu

lts/C

omm

ents

Dete

ctin

g re

curr

ence

s ov

eral

l** (5

5 pa

tient

s w

ith re

curr

ence

s, 6

with

sca

r)PE

T: S

e=98

%; S

p=83

%CT

: in

suffi

cient

dat

a to

cal

cula

te re

sults

CTAP

: ins

uffic

ient d

ata

to c

alcula

te re

sults

Dete

ctin

g liv

er le

sion

s** (

104

mal

igna

nt le

sion

s, 2

3 be

nign

lesi

ons)

PE

T: S

e=91

%; S

p=96

%; a

ccur

acy=

92%

CT:

Se=8

1%; S

p=60

%; a

ccur

acy=

78%

CTAP

: Se=

97%

; Sp=

5%; a

ccur

acy=

80%

Exclu

ding

les

ions

< 1

cm

(18

mal

igna

nt, 5

ben

ign)

PET:

Se=

99%

; acc

urac

y=98

%CT

: Se=

87%

; acc

urac

y=83

%CT

AP:

Se=9

7%; a

ccur

acy=

80%

Oth

er fi

ndin

gs•

If on

ly hi

stol

ogica

lly p

rove

n le

sions

wer

e in

clude

d, te

st c

hara

cter

istics

rem

aine

d wi

thin

1%

of a

bove

val

ues,

but

no

data

ava

ilabl

e to

repl

icate

calcu

latio

ns•

Accu

rate

diffe

rent

iatio

n of

pos

tsur

gica

l cha

nges

from

mal

igna

nt re

curre

nce:

PET=

12/

14 si

tes;

CT=

7/11

site

s; C

TAP=

5/11

site

s

Dete

ctin

g ex

trahe

patic

lesi

ons*

*(34

mal

igna

nt le

sion

s, 5

ben

ign

lesi

ons)

PET:

Se=

100%

CT:

Se=7

4%

Qua

ntita

tive

anal

ysis

of h

epat

ic le

sion

s**

• SU

R m

align

ant =

8.1

± 4

.1 v

s. SU

R be

nign

= 2.

0 ±

1.0

(p<

0.00

01)

• Fo

r ext

rahe

patic

lesio

ns th

e SU

R wa

s le

ss h

elpf

ul th

an C

T in

diffe

rent

iatin

gbo

wel u

ptak

e fro

m m

etas

tase

s

Ther

apeu

tic e

ffica

cy**

• PE

T he

lped

to p

lan s

urge

ry b

y ide

ntify

ing s

ite o

f rec

urre

nce

in 10

% o

f pat

ients

(n=6

)•

PET

helpe

d to

avo

id un

nece

ssar

y su

rger

y in

18%

of p

atien

ts (n

=11)

• Im

pact

of fa

lse p

ositiv

e an

d fa

lse n

egat

ive P

ET s

cans

on

patie

nt m

anag

emen

twa

s no

t rep

orte

d

**No

te:

PET

utilit

y wa

s ev

alua

ted

com

plem

enta

ry to

dia

gnos

tic te

sts

done

ear

lier

in th

e wo

rk u

p.

Patie

nts/

Met

hods

Purp

oses

Pros

pect

ive a

sses

smen

t:•

To a

sses

s th

e ac

cura

cy o

f FDG

PET

vs.

CT v

s. CT

arte

rial p

orto

grap

hy (C

TAP)

in d

etec

ting

liver

met

asta

ses

• To

ass

ess

the

accu

racy

of F

DG P

ET v

s. CT

in d

etec

ting

extra

hepa

tic m

etas

tase

s•

To e

valu

ate

the

impa

ct o

n m

anag

emen

t of p

atie

nts

with

recu

rrent

col

orec

tal c

arcin

oma

(retro

spec

tive)

Case

s52

con

secu

tive

patie

nts

pres

ente

d on

61

occa

sions

for e

valu

atio

n of

sus

pect

ed re

curre

nt c

arcin

oma

base

d el

evat

ed C

EA le

vels

or a

bnor

mal

find

ings

on

CT (i

nclu

des

9 re

peat

pat

ient

s)•

45 h

ad liv

er m

etas

tase

s, inc

luding

16

with

con

com

itant

extr

ahep

atic

disea

se, 1

0 ha

d ex

trahe

patic

dise

ase

only

• To

tal li

ver l

esio

ns:

104

mal

igna

nt, 2

3 be

nign

(0.

3 cm

-6 c

m in

size

)•

Tota

l ext

rahe

patic

lesio

ns:

34 m

alig

nant

, 5 b

enig

n•

Beni

gn c

ondi

tions

: No

rmal

liver

(7),

Post

-sur

gica

l site

(8),

Loca

l fib

rosis

(2),

Reso

lving

abs

cess

(1),

hepa

tic c

yst (

1), h

emat

oma

(1)

• 31

men

, 21

wom

en; M

ean

age

63 ±

11

yrs

Met

hods

• 40

pat

ient

s un

derw

ent a

bdom

inal

CT;

CT

porto

grap

hy=4

0; o

r bot

h=29

• PE

T, C

T, a

nd C

T po

rtogr

aphy

(bot

h wi

th c

ontra

st) p

erfo

rmed

with

in 2

mon

ths

of e

ach

othe

r•

Patie

nts

with

abn

orm

al PE

T sc

ans

in ex

tra-a

bdom

inal a

reas

had

add

itiona

l CT

scan

of t

hat r

egion

• PE

T vis

ually

inte

rpre

ted,

and

ana

lyzed

sem

iqua

ntita

tivel

y us

ing

SUR

corre

cted

for b

ody

weig

ht,

by tw

o nu

clear

med

icine

phy

sicia

ns; S

UR c

alcu

latio

ns e

xclu

ded

lesio

ns <

1 c

m in

dia

met

er•

CT a

nd C

T po

rtogr

aphy

inte

rpre

ted

inde

pend

ently

by

two

expe

rienc

ed ra

diol

ogist

s•

All r

eade

rs b

linde

d to

oth

er im

aging

resu

lts•

Dise

ase

conf

irmed

with

clin

ical o

r rad

iolo

gic

follo

w up

(n=1

7) o

r hist

opat

holo

gy o

btai

ned

surg

ically

(n=4

4) ,

exce

pt fo

r two

lesio

ns th

at w

ere

exam

ined

afte

r per

cuta

neou

s fin

e ne

edle

asp

iratio

n•

Surg

ical e

xam

and

intra

oper

ative

ultr

asou

nd u

sed

to c

onfir

m n

onre

secte

d liv

er le

sions

• Re

curre

nce

defin

ed p

atho

logi

cally

or b

y su

spec

ted

recu

rrenc

e on

imag

ing

• Ch

ange

s in

patie

nt m

anag

emen

t ret

rosp

ectiv

ely re

viewe

d wi

th th

e su

rgeo

ns

Lim

itatio

ns o

f Stu

dy D

esig

n•

High

pre

vale

nce

of m

alig

nanc

y an

d un

clear

pat

ient

sou

rce

(pot

entia

l ref

erra

l bia

s)•

Stro

ng a

ssoc

iation

bet

ween

imag

ing re

sults

and

cho

ice o

f pat

ient c

ohor

t; CT

of e

xtrah

epat

icar

eas

depe

nden

t on

PET

resu

lts (w

ork

up b

ias, m

inim

ized

by fo

llow

up o

f all p

atien

ts)•

Crite

ria fo

r pos

itive

test

and

cut

-off

for s

emiq

uant

itativ

e an

alys

is no

t rep

orte

d (p

oten

tial t

est r

evie

wbi

as)

• Bl

indi

ng to

oth

er c

linica

l info

rmat

ion

not r

epor

ted

(pot

entia

l tes

t rev

iew

bias

)•

Asso

ciatio

n be

twee

n im

agin

g te

st re

sults

and

gol

d st

anda

rd d

eter

min

atio

n un

clear

(pot

entia

ldi

agno

stic

revie

w bi

as)

• De

tails

of m

etho

ds fo

r eva

luat

ing

ther

apeu

tic e

ffica

cy n

ot re

porte

d

Dia

gn

ost

ic A

ccu

racy

an

d T

her

apeu

tic

Eff

icac

y S

tud

ies

of

FD

G P

ET

in C

olo

rect

al C

ance

r

Stud

y

Delb

eke

et a

l. (1

997)

(Van

derb

ilt Un

ivers

ityM

edica

l Cen

ter,

Nash

ville

, Ten

ness

ee)

December 1998


Resu

lts/C

omm

ents

Defin

ing

loca

l pel

vic

recu

rren

ce (2

1 di

seas

e, 2

6 no

dis

ease

)PE

T+CT

: Se

=90%

*; Sp

=100

%; P

PV=1

00%

; NPV

=93%

; Acc

=96%

CT:

Se=5

7%*;

Sp=8

1%; P

PV=7

1%; N

PV=7

0%; A

cc=7

0%*(

P =

0.00

8)•

PET

corre

ctly

iden

tified

pre

senc

e of

dise

ase

in a

ll pat

ient

s wi

th tr

ue p

ositiv

e CT

findin

gs•

PET

was

usef

ul in

diffe

rent

iatin

g po

stop

erat

ive fi

bros

is fro

m re

curre

nce

in 6

patie

nts

with

pos

itive

CT s

cans

• PE

T co

nfirm

ed d

iseas

e in

4 p

atie

nts

with

equ

ivoca

l CT

findi

ngs

• 2

false

neg

ative

s on

bot

h PE

T an

d CT

wer

e dif

fuse

mes

orec

tal a

nd a

nasto

mot

ichi

stol

ogie

s pr

oven

by

trans

rect

al U

S-gu

ided

bio

psie

s.

Defin

ing

hepa

tic m

etas

tase

s (2

3 di

seas

e, 3

5 no

dis

ease

)PE

T+CT

: Se

=96%

*; Sp

=100

%; P

PV=1

00%

; NPV

=97%

; Acc

=98%

CT:

Se=7

4%*;

Sp=8

6%; P

PV=7

7%; N

PV=8

3%; A

cc=8

1%*(

P =

0.02

)•

PET

iden

tified

all 5

pat

ient

s wi

th s

olita

ry m

etas

tase

s, C

T id

entifi

ed 2

pat

ient

swi

th so

litary

met

s•

PET

ident

ified

17/1

8 pa

tient

s an

d CT

iden

tified

10/

18 p

atien

ts wi

th m

ultipl

eles

ions

• 0n

e fa

lse n

egat

ive o

n bo

th C

T an

d PE

T fo

und

to b

e m

ultip

le s

uper

ficia

l hep

atic

lesio

ns u

p to

3 c

m in

dia

met

er

Defin

ing

extra

hepa

tic m

etas

tase

s (2

0 di

seas

e, 3

8 no

dis

ease

)PE

T id

entifi

ed e

xtra

-hep

atic

met

asta

ses

in 2

1 sit

es in

20

patie

nts,

of w

hich

9les

ions

were

miss

ed o

n CT

or C

XR__

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

__

Th

erap

eutic

effi

cacy

PE

T inf

luenc

ed c

linica

l man

agem

ent i

n 47

% (1

0/21

) pat

ients

with

loca

l rec

urre

ntdi

seas

e, 4

3% (1

0/23

) with

hep

atic

met

asta

ses,

and

38%

(8/2

0) w

ith e

xtra

hepa

ticm

etas

tase

s

Patie

nts/

Met

hods

Purp

ose

Retro

spec

tive

asse

ssm

ent:

• To

eva

luat

e PE

T ve

rsus

CT

for s

tagi

ng re

curre

nt a

nd m

etas

tatic

col

orec

tal c

ance

rs•

To a

sses

s th

e im

pact

of P

ET o

n cli

nica

l man

agem

ent o

f pat

ient

s wi

th c

olor

ecta

l can

cer

Case

s58

pat

ients

had

PET

betw

een

1/91

and

1/9

5 fo

r eva

luatio

n of

sus

pecte

d re

curre

nt (n

=47)

or

adva

nced

prim

ary

(n=1

1) d

iseas

e:

• ba

sed

on h

igh

clini

cal s

uspi

cion

and

equi

voca

l or p

ositiv

e CT

find

ings

(n=3

9) o

r clin

ical

susp

icion

alon

e, in

cludin

g ra

ised

CEA

levels

with

nor

mal

CT (n

=19)

• 33

men

, 25

wom

en; m

ean

age

60 y

rs. (

23-8

1 yr

s)•

beni

gn c

ondi

tions

not

repo

rted

in re

prod

ucib

le d

etai

l

Met

hods

• Al

l pat

ient

s un

derw

ent c

olon

osco

py a

nd c

ontra

st C

T of

che

st, a

bdom

en a

nd p

elvis

with

in 4

wks

prio

r to

PET

• CT

inte

rpre

ted

for e

xtent

of l

ocal

pelvi

c re

curre

nce

and

pres

ence

of m

etas

tase

s•

Qua

litativ

e PE

T in

terp

rete

d by

two

read

ers

with

acc

ess

to C

T re

sults

• M

alig

nanc

y=FD

G u

ptak

e m

oder

atel

y or

mar

kedl

y in

tens

e; b

enig

n=no

or m

ild u

ptak

e, o

r if

abno

rmal

ity id

entifi

ed o

n ot

her i

mag

ing

for w

hich

no

corre

spon

ding

abn

orm

ality

was

pre

sent

on

PET

• G

old

stan

dard

= su

rger

y, h

istol

ogy,

or b

oth

(n=4

0); c

linica

l and

radi

olog

ic fo

llow

up (n

=16)

;au

tops

y re

ports

(n=2

), an

d tre

atm

ent o

utco

mes

• Al

l pat

ients

follo

wed

for a

t lea

st 12

mon

ths

afte

r PET

or u

ntil d

eath

• Im

pact

of P

ET o

n pa

tient

man

agem

ent w

as a

sses

sed;

pos

itive

impa

ct=a

ltera

tion

in c

linica

lde

cisio

ns w

ith P

ET re

sults

Lim

itatio

ns o

f stu

dy d

esig

n•

? Co

nsec

utive

ser

ies•

Retro

spec

tive

anal

ysis

• Hi

gh p

reva

lenc

e of

mal

igna

ncy

(pot

entia

l ref

erra

l bia

s)•

Stro

ng a

ssoc

iatio

n be

twee

n te

st re

sults

and

cho

ice o

f pat

ient

coh

ort (

work

-up

bias

, min

imize

d by

follo

w up

of a

ll sub

jects

for a

t lea

st 12

mon

ths

afte

r pet

or u

ntil d

eath

)•

Crite

ria fo

r pos

itive

resu

lt on

imag

ing

not r

epor

ted

• Bl

indi

ng n

ot re

porte

d; c

t res

ults

ava

ilabl

e to

pet

read

ers

(test

revie

w bi

as)

• In

crem

enta

l valu

e of

pet

not

ass

esse

d•

Asso

ciatio

n be

twee

n te

st re

sults

and

gol

d st

anda

rd d

eter

min

atio

n un

clear

(pot

entia

l dia

gnos

ticre

view

bias

)•

Met

hods

for a

sses

sing

ther

apeu

tic e

fficac

y no

t rep

orte

d

Stud

y

Ogu

nbiyi

et a

l. (1

997)

(Was

hing

ton

Univ.

Scho

ol o

f Med

icine

, St.

Loui

s, M

issou

ri)

December 1998


Resu

lts/C

omm

ents

Dete

ctin

g re

curre

nt d

isea

se (1

5 re

curre

nce,

7 n

o re

curre

nce)

PET:

Se=

100%

; Sp=

71%

; PPV

=89%

; NPV

=100

%•

2 fa

lse p

ositiv

es d

ue to

asy

mm

etric

acti

vity

in bo

wel a

nd b

ladde

r dive

rticu

lum,

and

incre

ased

upt

ake

in do

me

of liv

er in

a p

atien

t in

whom

a p

oor q

uality

PET

scan

was

pro

duce

d du

e to

larg

e pa

tient

size

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

Th

erap

eutic

effi

cacy

• G

uided

by

the

PET

resu

lts, c

urat

ive s

urge

ry w

as a

ttem

pted

in o

nly 4

or 1

5pa

tient

s wi

th d

iseas

e•

Neith

er fa

lse p

ositiv

es o

n P

ET re

sulte

d in

mism

anag

emen

t; bo

th p

atie

nts

had

equi

voca

l fin

ding

s, a

nd re

ferri

ng p

hysic

ians

opt

ed fo

r add

itiona

l rad

iolo

gic

and

follo

w up

stu

dies

• Al

l 5 p

atie

nts

with

neg

ative

PET

sca

ns w

ere

alive

and

dise

ase

free

9-24

mon

ths

afte

r PET

; 2 p

atie

nts

had

nega

tive

biop

sy o

f ana

stom

otic

site,

oth

er 3

patie

nts

had

no d

iseas

e pr

ogre

ssion

on

follo

w up

*Not

e: o

verla

ppin

g pa

tient

pop

ulat

ions

with

pre

vious

stu

dy

Patie

nts/

Met

hods

Pu

rpos

eTo

retro

spec

tivel

y as

sess

PET

in p

atie

nts

with

une

xpla

ined

risin

g ca

rcin

oem

bryo

nic

antig

en (C

EA)

leve

ls af

ter t

reat

men

t of c

olor

ecta

l can

cer

Ca

ses

22 o

f 128

pat

ients

with

a h

istor

y of

colo

recta

l car

cinom

a wh

o un

derw

ent P

ET fr

om 6

/93

to 6

/96,

were

enr

olle

d an

d we

re p

oten

tial c

andi

date

s fo

r exp

lora

tory

lapa

roto

my:

• all

had

plas

ma

CEA

level

> 5.

0 ng

/ml (

mea

n 25

ng/

ml),

nor

mal

imag

ing s

tudie

s, en

dosc

opy,

and

phys

ical e

xam

on

rout

ine fo

llow-

up•

all p

atien

ts ha

d no

rmal

CEA

levels

afte

r res

ectio

n of

their

prim

ary

tum

ors

• 17

men

, 5 w

omen

; age

s 17

-84

• Pr

imar

y sit

e: c

olon

(9),

rect

um (1

0), r

ecto

sigm

oid

(2),

appe

ndix

(1)

• St

age

B (1

0); S

tage

s C

(5),

C1 (2

), C2

(3);

Stag

e D

(2)

M

etho

ds•

Patie

nts

with

hist

ory

of re

ctal o

r rec

tosig

moid

car

cinom

a ha

d co

ntra

st CT

of c

hest,

abd

omen

,an

d pe

lvis

• Pa

tient

s wi

th h

istor

y of

col

on c

ance

r had

con

trast

CT

of a

bdom

en a

nd p

elvis

• CT

sca

ns p

erfo

rmed

≤ 4

wee

ks b

efor

e PE

T•

CT in

terp

rete

d in

“rou

tine

clini

cal f

ashi

on”

• PE

T int

erpr

eted

qua

litativ

ely in

“rou

tine

clinic

al fa

shion

”, inc

luding

cor

relat

ing w

ith C

T, a

nd b

yco

nsen

sus

of a

t lea

st tw

o re

ader

s•

PET

used

in tr

eatm

ent m

anag

emen

t at t

he d

iscre

tion

of th

e re

ferri

ng s

urge

on•

PET

corre

late

d wi

th h

istol

ogy,

long

term

radi

olog

ic an

d cli

nica

l fol

low-

up ≥

6 m

onth

s•

PET

true

posit

ive=c

onfir

mat

ion

by b

iops

y or

obv

ious

dise

ase

site

on fo

llow

up im

agin

g di

rect

edby

PET

and

with

in 6

mon

ths

of P

ET•

PET

true

nega

tive=

con

firm

ation

by

biops

y or

no

abno

rmali

ty ve

rified

by

othe

r im

aging

or

clinic

al fo

llow-

up w

ithin

6 m

onth

s of

PET

Li

mita

tions

of s

tudy

des

ign

• Re

trosp

ectiv

e an

alys

is•

High

pro

babi

lity o

f mal

igna

ncy

(pot

entia

l ref

erra

l bia

s)•

Met

hods

for i

mag

e in

terp

reta

tion

uncle

ar a

nd re

ader

s no

t blin

ded

to C

T(te

st re

view

bias

)•

Blin

ding

of P

ET re

sults

and

refe

renc

e st

anda

rd n

ot re

porte

d; s

trong

cor

rela

tion

betw

een

test

resu

lts a

nd g

old

stan

dard

det

erm

inat

ion

(dia

gnos

tic re

view

bias

)•

Met

hods

for s

yste

mat

ic as

sess

men

t of t

hera

peut

ic ef

ficac

y no

t rep

orte

d

Stud

y

Flan

agan

et a

l. (1

998)

(Was

hing

ton

Univ.

Scho

ol o

f Med

icine

, St.

Loui

s, M

issou

ri)

Documents

Technology Assessment Program Report No. 10