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

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Talk Overview

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

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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

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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

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AJCC-6 Staging

• T0 No tumor
• Tx Tumor by cytology but no lesion found
• Tis Carcinoma in situ
• T1 Smaller than 3cm
• T2 gt3cm 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
  lt2cm from carina, or causes total atelectasis of
  the lung
• T4 Invades mediastinal structures, trachea,
  vertebra, or carina or malignant effusion present

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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

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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

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

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1
5
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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

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Survival Data
Mountain, CF Revisions in the International
System for Staging Lung Cancer Chest 1997 111
1710-1717
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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

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Stage III management

• Stage IIIA- being elucidated
• neoadjuvant chemoradiotherapy
• radiotherapy alone
• chemoradiotherapy

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More Advanced Stages

• Stage IIIB
• Chemotherapy or chemoradiation
• Stage IV
• Chemotherapy

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Traditional Staging

• PE/ clinical exam/ history
• CXR
• CT scan
• Surgical Methods

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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

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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
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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

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CT scanning

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

Images taken from http//www.rctradiology.com/ctc
hest.html
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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

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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.

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• 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)

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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

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• 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

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

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

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Results

• Every primary tumor was detected

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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.
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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.
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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

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• 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)

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• 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.

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• 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

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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

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Dual PET/ CT Device
Source GE Medical Systems website.
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• 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

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• 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

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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 ()

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Extrathoracic mets

• All extrathoracic abnormalities were biopsied if
  possible to confirm malignancy

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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

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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

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

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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

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Nodal Staging Accuracy

• 37 patients had their nodal status confirmed
  histologically

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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

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

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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!

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Other Similar studies

• DAmico et al coregistered images detected more
  lesions than PET alone, with better resolution

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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.

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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?

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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, gt 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

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• 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

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• 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

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Thanks
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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

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• 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