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PET scanning for staging of Non Small Cell Lung Cancer

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Title: PET scanning for staging of Non Small Cell Lung Cancer


1
PET scanning for staging of Non- Small Cell Lung
Cancer
  • Giancarlo Pillot
  • 12 Sep 2003

2
Talk Overview
  • Background Statistics
  • Staging Overview
  • Traditional Staging methods
  • Clinical Exam and history
  • CXR
  • CT Chest
  • Surgical Staging

3
Talk Overview
  • PET scanning
  • Physics
  • Staging Trials
  • "Preoperative Staging of Non- Small Cell Lung
    Cancer with PET"
  • Co- registered images trial
  • Staging of Non-Small Cell Lung Cancer with
    Integrated Positron- Emission Tomography and
    Computed Topography
  • Future directions

4
Background
  • Lung cancer (of all types) is the second most
    common malignancy and the leading cause of cancer
    death
  • Lung cancer mortality rate is 56.8per 100,000 in
    2000, with an incidence of 65.5/ 100,000 (males
    and females, all age groups)
  • Survival (and management) are closely correlated
    to stage

5
AJCC-6 Staging
  • T0 No tumor
  • Tx Tumor by cytology but no lesion found
  • Tis Carcinoma in situ
  • T1 Smaller than 3cm
  • T2 3cm or Involves the main bronchus, 2 cm or
    more distal to the carina or invades the visceral
    pleura, or with atelectasis extending to the
    hilum
  • T3 Extends to chest wall, diaphram, pericardium,
    or mediatinal pleura or is a main bronchus tumor
    the lung
  • T4 Invades mediastinal structures, trachea,
    vertebra, or carina or malignant effusion present

6
Nodes
  • NX Cannot assess regional nodes
  • N0 No regional lymph nodes
  • N1 Metastasis to ipsilateral peribronchial and/or
    ipsilateral hilar lymph nodes, and intrapulmonary
    nodes (even if directly invaded by primary tumor)
  • N2 Metastasis to ipsilateral mediastinal and/or
    subcarinal lymph nodes
  • N3 Metastasis to contralateral mediastinal or
    hilar nodes, ipsilateral or contralateral
    scalene, or supraclavicular lymph nodes

7
Stages
  • I T1-2, N0,M0
  • II T1-2, N1,M0
  • T3, N0, M0
  • IIIA T3, N1,M0
  • T1-3,N2,M0
  • IIIB Any T4, Any N3, M0
  • IV Any M1

8
  • Lababede, Omar, Meziane, Moulay A., Rice, Thomas
    W. TNM Staging of Lung Cancer A Quick Reference
    Chart Chest 1999 115 233-235

9
1
5
23
39-55
57-67
  • Lababede, Omar, Meziane, Moulay A., Rice, Thomas
    W. TNM Staging of Lung Cancer A Quick Reference
    Chart Chest 1999 115 233-235

10
Survival Data
Mountain, CF Revisions in the International
System for Staging Lung Cancer Chest 1997 111
1710-1717
11
Management by Stage
  • Stage I II- Surgical (or definitive XRT)
  • Individual trials of adjuvant radiotherapy did
    show an improvement in local recurrence, but
    failed to demonstrate a survival advantage.
    Metanalysis of adjuvant trials suggest that there
    may even be a survival disadvantage to
    radiotherapy. Postoperative radiotherapy in
    non-small-cell lung cancer systematic review and
    meta-analysis of individual patient data from
    nine randomised controlled trials. PORT
    Meta-analysis Trialists Group. Lancet 352 (9124)
    257-63, 1998.
  • A trial comparing cisplatin/ etoposide
    chemoradiotherapy to radiotherapy alone
    demonstrated no difference in survival nor
    recurrence. Keller, Steven M., Adak, Sudeshna,
    Wagner, Henry, Herskovic, Arnold, Komaki,
    Ritsuko, Brooks, Burke J., Perry, Michael C.,
    Livingston, Robert B., Johnson, David H., The
    Eastern Cooperative Oncology Group, A Randomized
    Trial of Postoperative Adjuvant Therapy in
    Patients with Completely Resected Stage II or
    IIIa Non-Small-Cell Lung CancerN Engl J Med 2000
    343 1217-1222

12
Stage III management
  • Stage IIIA- being elucidated
  • neoadjuvant chemoradiotherapy
  • radiotherapy alone
  • chemoradiotherapy

13
More Advanced Stages
  • Stage IIIB
  • Chemotherapy or chemoradiation
  • Stage IV
  • Chemotherapy

14
Traditional Staging
  • PE/ clinical exam/ history
  • CXR
  • CT scan
  • Surgical Methods

15
Clinical History and Exam
  • Good for evaluating for distant disease
  • Most guidelines suggest routine imaging for
    distant metastasis only if there is a compelling
    reason to do so
  • Silvestri, et al. The clinical evaluation for
    detecting metastastatic lung cancer a
    metanalysis. Am J Resp Care Med 1995 152225-230

16
Chest X-Ray
  • Poor at differentiating structures
  • Will not detect small involved nodes nor provide
    precise locations

Image taken from http//uwcme.org/courses/radiolo
gy/threehourtour/interpretation/commonchest/neopla
sia.html
17
CT Scanning
  • Criteria for positivity rely on size (short axis
    greater than 1 cm)
  • series (by Pieterman, et al) suggest that
    sensitivity and specificity for detecting lymph
    node metastases are approximately 75 and 66
    metanalysis by Dwamena is similar

18
CT scanning
  • All patients should undergo CT scan as an initial
    staging evaluation

Images taken from http//www.rctradiology.com/ctc
hest.html
19
Surgical Staging
  • Possibilities include mediastinoscopy,
    thoracoscopy, transbronchial needle aspiration,
    and endoscopic ultrasound with fine needle
    aspiration
  • Final surgical stage often differs from initial
    clinical stage

20
PET Scanning
  • In lung tumors, 18F-fluorodeoxyglucose is used as
    the tracer molecule.
  • This reflects the preferential metabolism of
    glucose in tumor cells.
  • When Phosphorylated, it is trapped within the
    cell and is not immediately metabolized.
  • It then releases a positron, which then reacts
    with an electron, releasing gamma rays.
  • However, there is also uptake by inflammatory
    processes, myocardium, and brain.

21
  • Motion artifact in the lungs will cause the
    positron signal to move, and thus limit size of
    lesions able to be detected (typically 1cm).
  • In the mediatinum, lesions as small as 0.5cm may
    be detected (less motion artifact)

22
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23
Traditional PET as staging
  • Jul 2000 paper in NEJM "Preoperative Staging of
    Non- Small Cell Lung Cancer with PET"
  • Potentially resectable NSCLCa patients undergoing
    evaluation for resection

24
  • All patients evaluated by clinical history and
    exam, labs, CT chest, bronchoscopy, cervical
    mediastinoscopy
  • led to TNM classification
  • medisatinoscopies included abnormal nodes on CT
    as well as abnormal and normal nodes by physical
    appearance

25
  • PET performed on all patients
  • PET reviewed by by observers blinded to patient
    data

26
  • 110 consecutive patients evaluated NSCLCa
    diagnosed in 102
  • 97 of reachable lymph node levels were dissected

27
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28
Results
  • Every primary tumor was detected

29
Lymph node detection
Pieterman RM, van Putten JWG, Meuzelaar JJ, et
al. Preoperative staging of non-small-cell lung
cancer with positron-emission tomography. N Engl
J Med 2000343254-261.
30
Lymph node detection
Pieterman RM, van Putten JWG, Meuzelaar JJ, et
al. Preoperative staging of non-small-cell lung
cancer with positron-emission tomography. N Engl
J Med 2000343254-261.
31
Results
  • False positive results noted in 10 cases
    silicoanthracosis (3), reactive hyperplasia(7).
  • False negative results noted in those with
    micrometastases in two and inability to
    distinguish between mediastinal invasion and
    tumor in one patient.
  • False positive results noted in 10 cases
    silicoanthracosis (3), reactive hyperplasia(7).
  • 29 hotsposts noted outside chest. 20 were mets.
  • excluded those with mets correctly in all 79
    patients

32
  • In comparison, CT identified 46 of 70 patients
    who did not have medisatinal mets, and 24 of 32
    who did have mediatinal mets.
  • Sensitivity and specificity were 75 and 66
  • Overall sens/ spec for PET in detecting mets/
    nodes was 95 and 83
  • Staging was changed by PET in 62 of 102 patients
    (20 lower/ 42 higher)

33
  • Note that 17 of patients would have been denied
    potentially curative surgery if follow up biopsy
    of lymph nodes had not been performed to rule out
    false positive tests.

34
  • Subsequent series have validated the concept that
    PET scan as an initial nonsurgical evaluation in
    NSCLCa is a reasonable strategy
  • Harm van Tinteren, Otto S Hoekstra, Egbert F
    Smit, Jan H A M van den Bergh, Ad J M Schreurs,
    Roland A L M Stallaert, Piet C M van Velthoven,
    Emile F I Comans, Fred W Diepenhorst, Paul
    Verboom, Johan C van Mourik, Pieter E Postmus,
    Maarten Boers, Gerrit J J Teule, and the PLUS
    study group Effectiveness of positron emission
    tomography in the preoperative assessment of
    patients with suspected non-small-cell lung
    cancer the PLUS multicentre randomised trial
    Lancet 2002 359 1388-1393

35
Coregistered PET/ CT scan
  • In order to attempt to overcome the poor
    localization of possible tumor sites by PET scan,
    devices have been made that integrate PET and CT
    scan in the same machine

36
Dual PET/ CT Device
Source GE Medical Systems website.
37
  • 19 Jun 2003 NEJM article Staging of Non-Small
    Cell Lung Cancer with Integrated Positron-
    Emission Tomography and Computed Topography
  • Evaluated Diagnostic Accuracy of Integrated CT/
    PET as compared to correlation of CT and PET alone

38
  • Enrolled 50 patients referred for surgery with
    proven or suspected NSCLCa at University Hospital
    of Zurich.
  • All patients underwent conventional staging as
    well as integrated CT- PET
  • Used unenhanced CT combined with PET scanning

39
Resections
  • Lung resections with mediastinal lymph node
    dissection
  • 35patients lung resection lymphadenectomy
  • 3 patients ex thoracotamy
  • 2 patients wedge resection (no node resection)
  • 8 patients extrathoracic mets detected
  • 1 patient pleural fluid ()

40
Extrathoracic mets
  • All extrathoracic abnormalities were biopsied if
    possible to confirm malignancy

41
Image Review
  • Images prospectively analyzed by two independent
    review boards (clinical data blinded)
  • Board 1 reviewed CT, assigned stage, then read
    PET, reassigned stage
  • Board 2 Analyzed PET first, assigned stage, then
    combined images with reassigned stage
  • If Stage could not clearly be assigned, both
    likely stages were noted

42
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43
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44
Results
  • 20/49 patients had additional information
    provided by PET (24 events)
  • 9 patients exact lymph node location
  • 3 patients evaluation of chest wall invasion
  • 3 patients mediastinal invasion
  • 7 patients differentiated tumor from
    inflammation/ atelectasis
  • 2 patients revealed distant metastasis

45
  • 40 patients had their tumor stage confirmed
    histologically
  • These were the patients whose scans were
    evaluated for diagnostic accuracy in terms of
    pathologic staging

46
Accuracy of Tumor Staging
  • Lardinois,et al. Staging of Non-Small-Cell Lung
    Cancer with Integrated Positron-Emission
    Tomography and
  • Computed Tomography N Engl J Med 2003 348
    2500-2507

47
Nodal Staging Accuracy
  • 37 patients had their nodal status confirmed
    histologically

48
Accuracy of Nodal Staging
  • Lardinois,et al. Staging of Non-Small-Cell Lung
    Cancer with Integrated Positron-Emission
    Tomography and Computed Tomography N Engl J Med
    2003 348 2500-2507

49
  • 1 contralateral mediastinal node involvement/
    false ()
  • 2 hilar extension of tumor/ false ()
  • 3 no uptake in nodes that were true involved/
    false (-)

50
Interobserver Variability
  • Kappa ratings were compared between both groups
    of reviewers with no significant difference in
    accuracy between the two boards (based on the PET
    ratings)
  • However, this study could still be theoretically
    comparing the skills of the two reviewer groups!

51
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52
Other Similar studies
  • DAmico et al coregistered images detected more
    lesions than PET alone, with better resolution

53
Cost effectiveness
  • Cost effectiveness studies have been done and
    have a reasonable cost- effectiveness strategy
  • Scott WJ Shepherd J Gambhir SS
    Cost-effectiveness of FDG-PET for staging
    non-small cell lung cancer a decision analysis.
    Ann Thorac Surg 1998 Dec66(6)1876-83
    discussion 1883-5.

54
Issues/ Questions
  • Given that combined PET CT still miss a small
    number of mediatinal nodes, many surgeons still
    perform mediatinoscopy prior to surgery even with
    a negative PET scan
  • Is there a difference between PET negative N2
    disease and PET positive N2 disease in prognosis
    or response to therapy?

55
Review of Current Staging Recommendations
  • For patients with either a known or suspected
    lung cancer who are eligible for treatment, a CT
    scan of the chest should be performed. Level of
    evidence, fair benefit, substantial grade of
    evidence, B
  • In patients with enlarged mediastinal lymph nodes
    on CT scans (ie, 1 cm on the short axis),
    further evaluation of the mediastinum should be
    performed prior to surgical resection of the
    primary tumor. Level of evidence, fair benefit,
    substantial grade of evidence, B
  • For patients who are operative candidates, where
    available, a whole-body FDG-PET scan is
    recommended to evaluate the mediastinum. Level of
    evidence, fair benefit, substantial grade of
    evidence, B
  • In patients with abnormal results of FDG-PET
    scanning, further evaluation of the mediastinum
    with sampling of the abnormal lymph node should
    be performed prior to surgical resection of the
    primary tumor. Level of evidence, fair benefit,
    substantial grade of evidence, B

56
  • For patients with either a known or suspected
    lung cancer who are eligible for treatment, an
    MRI of the chest should not be performed for
    staging the mediastinum but should be performed
    in patients with NSCLC involving the superior
    sulcus for evaluation of the brachial plexus or
    for evaluation of vertebral body invasion. Level
    of evidence, fair benefit, substantial grade of
    evidence, B
  • For patients with either a known or suspected
    lung cancer, a thorough clinical evaluation
    similar to that listed in Table 2 should be
    performed. Level of evidence, good benefit,
    substantial grade of evidence, A
  • Patients with abnormal clinical evaluations
    should undergo imaging for extrathoracic
    metastases. Site-specific symptoms warrant
    directed evaluation of that site with the most
    appropriate study (eg, head CT scan, bone scan,
    and abdominal CT scan). Level of evidence, good
    benefit, substantial grade of evidence, A
  • Patients with clinical stage I or II lung cancer
    and a normal clinical evaluation require no
    further imaging for extrathoracic disease. Level
    of evidence, good benefit, substantial grade of
    evidence, A

57
  • Patients with stage IIIA and IIIB disease should
    have routine imaging for the detection of
    extrathoracic metastases (eg, head CT scan, bone
    scan, and abdominal CT scan). Level of evidence,
    poor benefit, substantial grade of evidence, C
  • Patients with abnormal imaging study results
    should not be excluded from potentially curative
    surgery without tissue confirmation or
    overwhelming clinical and radiographic evidence
    of metastases. Level of evidence, good benefit,
    substantial grade of evidence, A

58
Thanks
59
Selected References
  • Surveillance, Epidemiology, and End Results
    (SEER) Program (www.seer.cancer.gov) SEERStat
    Database Mortality - All COD, Public-Use With
    State, Total U.S. (1969-2000), National Cancer
    Institute, DCCPS, Surveillance Research Program,
    Cancer Statistics Branch, released April 2003.
    Underlying mortality data provided by NCHS
    (www.cdc.gov/nchs).  
  • NCI website at www.nci.nih.gov, sections on lung
    cancer statistics
  • Lababede, Omar, Meziane, Moulay A., Rice, Thomas
    W. TNM Staging of Lung Cancer A Quick Reference
    Chart Chest 1999 115 233-235
  • Mountain, CF Revisions in the International
    System for Staging Lung Cancer Chest 1997 111
    1710-1717
  • Silvestri, Gerard A., Tanoue, Lynn T., Margolis,
    Mitchell L., Barker, John, Detterbeck, Frank The
    Noninvasive Staging of Non-small Cell Lung
    Cancer The Guidelines Chest 2003 123 147-156
  • Toloza, Eric M., Harpole, Linda, McCrory, Douglas
    C. Noninvasive Staging of Non-small Cell Lung
    Cancer A Review of the Current Evidence Chest
    2003 123 137-146
  • Pieterman, Remge M., van Putten, John W.G.,
    Meuzelaar, Jacobus J., Mooyaart, Eduard L.,
    Vaalburg, Willem, Koeter, Gerard H., Fidler,
    Vaclav, Pruim, Jan, Groen, Harry J.M.
    Preoperative Staging of Non-Small-Cell Lung
    Cancer with Positron-Emission Tomography N Engl J
    Med 2000 343 254-261
  • Lardinois, Didier, Weder, Walter, Hany, Thomas
    F., Kamel, Ehab M., Korom, Stephan, Seifert,
    Burkhardt, von Schulthess, Gustav K., Steinert,
    Hans C. Staging of Non-Small-Cell Lung Cancer
    with Integrated Positron-Emission Tomography and
    Computed Tomography N Engl J Med 2003 348
    2500-2507
  • Pieterman RM, van Putten JWG, Meuzelaar JJ, et
    al. Preoperative staging of non-small-cell lung
    cancer with positron-emission tomography. N Engl
    J Med 2000343254-261.
  • Dwamena BA, Sonnad SS, Angobaldo JO, Wahl RL.
    Metastases from non-small cell lung cancer
    mediastinal staging in the 1990s -- meta-analytic
    comparison of PET and CT. Radiology
    1999213530-536

60
  • Berlangieri, Salvatore U., Scott, Andrew M.
    Metabolic Staging of Lung Cancer N Engl J Med
    2000 343 290-292
  • D'Amico, Thomas A., Wong, Terence Z., Harpole,
    David H., Brown, Stephen D., Coleman, R. Edward
    Impact of computed tomography-positron emission
    tomography fusion in staging patients with
    thoracic malignancies Ann Thorac Surg 2002 74
    160-163
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