1. Using PET in Lung Cancer
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2. Oncology Imaging Computed Tomography (CT) Photon attenuation Anatomy
Magnetic Resonance (MR) Spin flip time Anatomy (blood flow)
Ultrasound (US) Sound attenuation Anatomy
Conventional Nuclear Radioactive tracer Function
Medicine (NM) uptake
Positron Emission Radioactive tracer Function
Tomography (PET) uptake
Function

3. 18F-FDG Pharmacokinetics
Plasma Cell
Glucose
FDG
Glucose-6-P
FDG-6-P
FDG participates in the first step of glucose metabolism, but cannot be further metabolized and is trapped inside the cell where it is retained in proportion to the rate of glycolosis.

4. Normal distribution pattern of 18F-FDG
After IV injection, FDG is distributed to all organs of the body in proportion to cellular glucose metabolism.
Normal biodistribution will demonstrate uptake in the brain, evidence of excretion via the urinary and GI systems, faint hepatic uptake, some bone & soft tissue uptake, and variable cardiac uptake
Cancer cells are highly metabolic and utilize glucose at 3-5x the rate of normal cells.

5. Oncology Imaging Clinical Applications of PET
Characterization of radiographic abnormalities
Detection of radiographically occult lesions
Staging – initial evaluation of the extent of disease
Restaging - evaluation of the extent of recurrent disease (resectability)
Evaluation of response to therapy 3

6. Characterization of Radiographic Abnormalities
66 yr old w/ ovarian cancer & brain mets treated w/stereotactic radiosurgery & chemotherapy; developed right hemiplegia 2 wks prior to PET. Treated w/steroids, symptoms resolved.
A new mass or nodule is identified by conventional imaging (x-ray, CT, MRI, US) and the physician needs to determine what it is.

7. Characterization of Radiographic Abnormalities
61 year old woman with ovarian cancer and brain metastases treated with whole brain and stereotactic radiation

8. Characterization of Radiographic Abnormalities
66 year old man with pancoast tumor of the right lung – new adrenal mass.
CT shows enlargement of the right adrenal gland, adenoma vs metastasis.

9. Accuracy of PET in characterizing adrenal masses
Differentiation of Benign from Malignant Adrenal Masses
Sensitivity Specificity
Yun % (18/18) 94% (30/32)
J Nucl Med 2001;42:1795
Erasmus % (23/23) 80% (8/10)
Am J Roentgenol 1997;168:1361
Maurea % (7/7) 100% (6/6)
Radiol Med 1996;92:782
Boland % (14/14) 100% (10/10)
Radiology 1995;194:131 3

10. Detection of a radiographically occult lesion
61 yr old man s/p partial colectomy for sigmoid cancer, rising CEA level to Negative CT, CEA scan, bone scan, colonoscopy. PET demonstrates FDG uptake; biopsy = adenocarcinoma.
Abnormal lab values or physical symptoms indicate possible cancer or cancer spread, but conventional imaging is normal

11. Staging after initial diagnosis of cancer
To determine extent of disease and select the most appropriate treatment course
Surgery
Induction chemo and/or radiation therapy prior to surgery
Systemic therapy
Palliative therapy
Images courtesy of Macapinlac, UT MD Anderson Cancer Center

12. Restaging a known or suspected recurrence
76 yr old with locally recurrent cervical cancer, CT shows pelvic adenopathy, scheduled for pelvic exenteration. PET positive for disease beyond pelvis.
To determine extent of disease, particularly if planned treatment is local/regional surgery or radiation therapy to confirm suspicion of recurrence

13. Restaging a known recurrence
Repeat positive right breast excisional biopsy.
Conventional imaging negative and pt scheduled for right mastectomy
PET results: Widespread liver metastases
7 cm abdominal mass (!)
Unsuspected left breast tumor
Bone metastases, left acetabulum
Impact: Mastectomy cancelled and chemotherapy initiated
Restaging a Known Recurrence
In this case, a patient with a history of Rt. Breast cancer, post wedge resection, chemo and radiation therapy, presented with elevated tumor markers and a new right breast mass. The excisional breast biopsy was positive for metastatic breast cancer. Restaging by conventional imaging was negative and she was scheduled for a mastectomy. Tumor markers remained elevated after the excisional biopsy (should have returned to zero if that were the sole metastatic lesion). PET was performed to confirm extent of disease prior to surgery. PET demonstrated widespread liver metastases, a 7 cm abdominal mass, unsuspected Lt breast tumor, and a bone lesion on the left acetabulum. Her mastectomy was cancelled and she received high dose chemotherapy.
Images courtesy of Landis K. Griffeth, MD, PhD, North Texas Clinical PET Institute

14. Restaging a known recurrence
Restaging at completion of therapy
The post treatment scan demonstrated complete resolution of her metastatic disease and confirmed the effectiveness of the chemotherapy.
Images courtesy of Landis K. Griffeth, MD, PhD, North Texas Clinical PET Institute

15. Evaluating response to therapy
To determine effectiveness of treatment and whether additional treatment is necessary
Testicular cancer patient with apparent complete response to chemotherapy
Images courtesy of Northern California PET Imaging Center

16. Lung Cancer Clinical Indications
FDG PET outperforms conventional imaging techniques for:
Characterization of a radiographically detected pulmonary nodule as malignant or benign
Initial staging or restaging to determine whether a lung tumor has metastasized to regional hilar or mediastinal nodes
Initial staging or restaging to determine whether a lung tumor has spread to distant sites
Monitoring response to therapy

17. Lung Cancer
Problem
Leading cause of cancer related death in the Western world
2008 – 215,020 newly diagnosed cases in the US
2008 – 161,840 patient deaths
Classified into two distinct malignancies:
Small cell cancers - 13%
Present as a central lesion, usually metastasized at presentation
Surgery rarely results in cure
Patients are almost always treated with chemo
PET results do not alter treatment choice
Source: American Cancer Society. Cancer Facts and Figures 2008

18. Lung Cancer Non-small cell lung cancer (NSCLC) – 87%
Adenocarcinoma – peripheral w/ early mets
Squamous cell – central, large tumor w/ late development of distant mets
Large cell carcinoma – commonly a large peripheral mass
Patients with operable NSCLC have a five-year survival rate of 49%
Only 16% of NSCLC patients are operable at diagnosis
Overall five-year survival is ~15% and has not changed in decades despite improved CT screening and aggressive treatment protocols
Source: American Cancer Society. Cancer Facts and Figures 2008

19. Lung Cancer
Goal NSCLC
Early identification of operable tumors & accurate tumor staging
Strongest prognostic factor in NSCLC
Guides treatment decisions, determines operability
Avoids clinical over staging (denies pts therapy w/ curative intent)
Avoids ineffective therapies (unnecessary thoracotomies)
Permits outcome comparisons
Allows selection of uniform patient populations for clinical trials

20. Lung Cancer Five year survival: highly correlated with stage
IA (T1N0M0): 67%
IIA (T1N1M0): 55%
IB (T2N0M0): 57%
IIB (T2N1M0 or T3N0M0): 38%
IIIA (T3N1M0 or T1-3N2M0): 23-25%
IIIB (T4N0-3M0 or T(1-3)N3M0): 3-7%
IV (Any T/N M1) 1%
Source: Chest 1997; (111):

21. Lung Cancer NSCLC management:
Stages I, II and selected IIIA (T3N1M0): surgical resection
Stage IIIA-N2: induction chemo and radiation therapy; possible surgery
Stage IIIB-N3: definitive chemo and radiation therapy
Stage IIIB-T4 and Stage IV: chemotherapy
Note: this is an aggressive surgical approach, since surgery is the only curative option
Source: Hubert Vesselle, PhD, MD, Role of PET in the Management of Pulmonary Nodules and Lung Cancer, University of Washington, June 2004

22. Lung Cancer NSCLC treatment decision points:
Evidence of distant metastases (M1)
Bone, liver, adrenal glands, brain
Evidence of malignant pleural implants (T4)
Presence of N2 or N3 mediastinal nodal disease
Source: Hubert Vesselle, PhD, MD, Role of PET in the Management of Pulmonary Nodules and Lung Cancer, University of Washington, June 2004

23. Lung Cancer Symptoms, physical findings – chest x-ray
Normal chest x-ray – lung cancer unlikely
Abnormal chest x-ray
Chest CT – findings are generally nonspecific and require confirmation (biopsy or PET)
Additional smaller lesions, some characterization
Invasion of tumor into chest wall, vertebrae or mediastinum
Lymph node evaluation (nodes > 1 cm need further evaluation)
Metastases to liver and adrenal glands

24. Lung Cancer Tissue identification – bronchoscopy or FNA
Mediastinoscopy – most accurate method for staging the superior mediastinal lymph nodes (anterior medistinotomy or video assisted thoracoscopy)
Thoracotomy – <5% for diagnosis & staging
Role for PET
To determine whether a lung tumor has metastasized to regional hilar or mediastinal nodes
To determine whether a lung tumor has spread to distant sites

25. Lung Cancer Staging 66 year old man, s/p lobectomy for lung cancer.
Has new right lung mass and positive sputum for squamous cell cancer.

26. Lung Cancer Staging after Initial Diagnosis
History: 49 year old man with new lung cancer
PET findings: Avid uptake in primary tumor and focal area of uptake in retroperitoneum.
PET•CT confirmed metabolic activity in the mass behind psoas muscle seen on contrast CT.
(This slide is animated-images and arrows appear on clicks)
This case is of a 49 year old man with new lung cancer. The PET scan demonstrated avid uptake in the primary tumor, but also a focal area of uptake in retroperitoneum. When fused, the PET•CT images confirmed metabolic activity in the mass behind psoas muscle seen on contrast CT.
PET.CT confirmed that the mass seen on the CT portion of the exam was metabolically active and provided the information required to determine the extent of disease and help select the most appropriate treatment course for this patient.

27. Lung Cancer Mediastinal Staging
Current summary of published data on mediastinal staging indicates a distinctly higher sensitivity and specificity for FDG PET than for CT. Many clinicians feel that these results are not sufficiently high to obviate the need for mediastinoscopy. FDG PET can be valuable in guiding mediastinal biopsies.
FDG PET CT
# of PTS Sens Spec Acc Sens Spec Acc
Source: Gambhir et al, J Nucl Med 2001; 42:1S-93S

28. Lung Cancer Extra-thoracic Staging
A summary of published data suggests remarkably high sensitivity and specificity for detection of sites of distant metastasis.
FDG PET CT
# of PTS Sens Spec Acc Sens Spec Acc
PET PPV = 93 NPV = CT PPV = 97 NPV = 79
Source: Gambhir et al, J Nucl Med 2001; 42:1S-93S

29. Lung Cancer PET Staging Accuracy
Pieterman, et al, prospectively compared the ability of standard staging approach (CT, US, bone scanning & biopsy if needed) with one involving PET to evaluate mediastinal LN and distant sites in 102 patients with resectable NSCLC.
Lymph node disease confirmed by histopathology (97% of the nodes were sampled)
Distant metastases evaluated w/ standard methods to detect occult metastases (xray, MRI, bone scan)
Source: Pieterman, et al: NEJM:343:4,2000 pp

30. Lung Cancer PET Staging Accuracy
Pieterman, et al. found that only PET results correlated with
histopathology for detection of mediastinal metastases:
FDG PET CT
# of PTS Sens Spec Sens Spec
% % % %
PET identified distant metastases in 11/102 patients (11%).
For detection of both mediastinal & distant metastatic disease:
Sensitivity of PET – 95%
Specificity of PET – 83%
Source: Pieterman, et al: NEJM:343:4,2000 pp

31. Lung Cancer PET Staging Accuracy
Use of PET resulted in a different stage from the one
determined by the standard approach in 62/102 patients
20 patients were down staged
42 patients were up staged
Conclusions
Whole-body PET can replace other types of imaging for all sites except the brain
Compared with traditional staging methods, PET can result in more accurate classification of the stage of disease in patients with presumed resectable NSCLC
Source: Pieterman, et al: NEJM:343:4,2000 pp

32. Images courtesy of Macapinlac, UT MD Anderson Cancer Center
Lung Cancer SPN
55 yr old man s/p Heimlich maneuver, with left rib pain
Chest x-ray reveals a new RUL mass
Images courtesy of Macapinlac, UT MD Anderson Cancer Center

33. Images courtesy of Macapinlac, UT MD Anderson Cancer Center
Lung Cancer Staging
Images courtesy of Macapinlac, UT MD Anderson Cancer Center

34. Lung Cancer Restaging
63 patients with suspected relapse > 6 months after attempted cure (definitive treatment of NSCLC). Compared conventional restaging with PET, 12 month follow up.
PET + PET -
Relapse (98% sensitivity)
No relapse (NPV 93%)
Total (4 not evaluable)
Source: Hicks et al, JNM 42:11, 2001 pp

35. Lung Cancer Restaging
PET resulted in a major management change in 40 patients (63%).
6 patients treatment changed from curative to palliative
3 patients treatment changed from palliative to curative
9 patients with negative PET were spared active intervention
Both the presence and the extent of relapse were highly significant prognostic factors.
Source: Hicks et al, JNM 42:11, 2001 pp

36. Lung Cancer Evaluation of Treatment Response
Images courtesy of Northern California PET Imaging Center

37. Lung Cancer Evaluation of Treatment Response
NSCLC Pre and Post Treatment Quantification
SUV = 13.9
SUV = 5.1
9/29/98
12/1/98
Images courtesy of Northern California PET Imaging Center

38. Lung Cancer RTP Planning
Radiation Treatment Planning in NSCLC using PET
Prospective study – 11 patients
Immobilized in treatment position, CT simulation performed followed by PET (same body cast)
PTV, GTV & normal organs delineated w/ CT data
CT & PET images registered - “fused” in treatment planning system
PTV modified with fused PET/CT data set
Results
7/11 had increase in PTV ~ of 19% to include distant nodal disease
4/11 had decrease in PTV ~ of 18% , exclusion of atelectasis & trimming to avoid delivering higher doses to cord & heart
Source: Erdi, et al. Radiother Oncol 2002 Jan: 62(1):51-60

39. Lung Cancer RTP Planning
Conclusions
PET data improves definition of primary lesion by including positive lymph nodes in PTV
PET reduces likelihood of geographic misses with improved chance of local control
Source: Erdi, et al. Radiother Oncol 2002 Jan: 62(1):51-60

40. Lung Cancer RTP Planning
Radiation Oncology department, Peter MacCallum Cancer Institute Melbourne, Australia
Prospective study of 153 patients w/ un-resectable NSCLC – candidates for RRT after conventional staging; restaged after PET
107 patients received radical therapies (70%)
102 = RRT with or without concurrent chemotherapy
5 = potentially curative resection after down staging by PET
46 patients received palliative RX (30%)
28 = PET detected distant metastasis
18 = PET detected extensive locoregional disease
Source: Cancer 2001 Aug 15:92(4):886-95

41. Lung Cancer Prognostic Value of PET
Prognostic Value of PET in NSCLC
Higashi et al showed:
SUV <5
86% 5 year disease free survival
SUV >5
17% 5 year disease free survival
Source: Higashi et al. JNM 2002; 43:39-45

42. Lung Cancer Impact of PET on RRT
Radiation Oncology department,
Peter MacCallum Cancer Institute Melbourne, Australia
Conclusion and impact of PET on radical RT
NSCLC staging w/ PET…….
Detected unsuspected metastasis in 20%
Strongly influenced choice of treatment strategy
Frequently impacted RT planning volumes
Powerful predictor of survival
Source: Cancer 2001 Aug 15:92(4):886-95

43. Lung Cancer Staging before RRT
Radiation Oncology department, Peter MacCallum Cancer Institute Melbourne, Australia
NSCLC Staging w/ PET: impact on survival s/p radical radiotherapy
30% of NSCLC RRT candidates became ineligible after PET staging
Compared two prospective cohorts –
1 = patients given 60 Gy conventionally fractionated RRT with or without concurrent carboplatin. Stage I-III, ECOG status 0 or 1, < 10% wt loss, not staged with PET – 77 patients
2 = all RRT candidates who received RRT after PET staging. Stage I-III, ECOG status 0 or 1, < 10% wt loss – 88 patients
Source: Int J Radiat Oncol Biol Phys 2002 Feb 1:52(2):351-61

44. Lung Cancer Staging Results
Patients selected for RRT after PET have lower early cancer mortality than those selected using conventional imaging.
PET Patients
Non-PET Patients
Median Survival
31 months
16 months
Mortality from NSCLC in 1st yr
17%
32%
Mortality from other causes 1st yr 8% 4%
Source: Int J Radiat Oncol Biol Phys 2002 Feb 1:52(2):351-61

45. Lung Cancer True Positive PET True Negative PET Primary lung cancer
Solitary pulmonary metastasis
True Negative PET
Benign lung nodules – granuloma, hamartoma
Inflammation
Scar, fibrosis
Treated, non-viable tumor

46. Lung Cancer False Positive PET
Infection – organizing pneumonia, fungal, granulamatous (TB, histoplasmosis, aspirgillosis)
Focal non-infectious lung inflammation
Normal lung s/p radiation therapy
Sarcoid nodule
Residual inflammation in treated lung cancer
False Negative PET
Slow growing lung cancer (BAC)
Slow growing metastasis
Well differentiated carcinoid
Acellular tumor
Small lesions, < 7mm

47. False Negative
History: Patient presented for evaluation of a pulmonary nodule
Findings: No FDG uptake seen within the right lower lobe pulmonary nodule
CT Guide Biopsy: Bronchoalveolar cell carcinoma
Discussion: A few tumor types may be missed on PET because they are less FDG avid than others
This case is an example of a false negative and illustrates how some tumors that are not intensely FDG avid, including bronchoalveolar carcinoma, may be missed on the PET scan because they are not FDG avid.
This patient with no significant past medical history was referred for a PET•CT scan for evaluation of pulmonary nodule. IMAGING FINDINGS: There was no FDG uptake seen within the right lower lobe pulmonary nodule. There was physiologic uptake present within the nasopharynx as well as in the muscles and fat within the neck. There were no areas of additional abnormal FDG uptake noted on this examination, with no evidence of FDG-avid malignancy. The physician recommended a three month follow up with CT. To confirm the diagnosis a CT-guided biopsy was performed and the results were consistent with bronchoalveolar cell carcinoma. FDG PET has a very high negative predictive value; however, it is important to keep in mind that there are a few tumor types that may be missed on PET because they are less FDG avid than most other malignancies. In the lung, bronchoalveolar cell carcinoma and other well-differentiated adenocarcinomas may appear with little or no FDG uptake. It is important in these cases to look at the CT characteristics for any specific characteristics that may suggest these primary tumors. Although this case showed no specific characteristics on CT, because it had grown slightly, a CT guided biopsy was performed.
Images courtesy of Todd Blodgett, MD, UPMC

48. False Positive
History: 83 year old woman with SPN in right upper lobe.
Findings: Intense increased uptake identified corresponding to the mass
CT Guide Biopsy: Active tuberculosis
Discussion: Several non-malignant processes can cause moderate to intense FDG uptake and can mimic malignancy
83 year old woman with a solitary pulmonary nodule in the posterior segment right upper lobe. She had a recent pneumonia and x-rays showed an abnormality. The chest x-ray showed opacity in the upper lobe. A CT scan showed it to be more of a solid density. It was compared to her previous CT scan and this upper lobe density appeared to be new. There were some other areas of scarring which were stable. IMAGING FINDINGS:There was intense increased FDG uptake identified corresponding to the right upper lobe lung mass. There is diffuse and prominent FDG uptake identified in the skeletal musculature of the neck, chest, and extremities. This is most likely secondary to physiologic FDG uptake. DISCUSSION: This is a case of a older woman who had been on some steroid therapy and was sent for PET•CT to evaluate a new slightly cavitary right upper lobe lesion. Everyone in this patient's care thought this was going to represent malignancy. The PET•CT even showed fairly intense FDG uptake within the nodule. However, this is a good example of a false positive case for malignancy. This turned out to be active TB. Unfortunately, the diagnosis was not considered earlier and this patient was sent for a CT-guided biopsy. Although PET and PET•CT are very good for distinguishing benign from malignant processes, there are several non-malignant processes that can cause moderate to intense FDG uptake and can mimic malignancy. Some of these include sarcoidosis, silicosis, rheumatoid nodules, other granulomatous process and infection.
Images courtesy of Todd Blodgett, MD, UPMC

49. Lung Cancer Summary
Perform PET in all potentially resectable NSCLCs to identify occult advanced disease (M1 & T4 pleural implants)
PET provides valuable information in mediastinal nodal staging to:
Direct surgical confirmation to LN stations not accessible by medistinoscopy
Guide mediastinoscopy to the nodal station of highest yield to increase sensitivity

50. Lung Cancer Summary
High accuracy and PPV of mediastinal staging by PET can be used to:
Optimally schedule OR time without a thoracotomy in PET positive N2-3 disease
High NPV of PET for mediastinal LN metastases can be used to forgo mediastinoscopy until resection
PET should be performed on patients w/ suspected recurrence if active treatment is considered
PET should be used to evaluate response to induction or directive therapy

51. PET in Oncology Summary
Clinical Applications of PET
Characterization of radiographic abnormalities
Detection of radiographically occult lesions
Staging – initial evaluation of the extent of disease
Restaging - evaluation of the extent of recurrent disease (resectability)
Evaluation of response to therapy
Benefits of PET Imaging
Impact on patient mgmt (identifies most appropriate course of treatment for a specific patient)
Avoid unnecessary biopsies or surgeries
Reduce patient risk, improves patient outcome
Determine patient response to therapy

52. PET in Oncology Summary
Every patient does not need PET, but many will benefit from the addition of PET into their staging/restaging work up
The information provided by PET and CT is complementary
PET is not perfect - there are false negative and false positive results
PET often changes the treatment plan, usually by avoiding futile surgery

53. PET in Oncology Conclusions
A negative PET scan usually eliminates the need for biopsy or surgery – avoid complications associated with unnecessary invasive procedures
A negative PET scan rules out cancer with a high degree of confidence
A positive PET scan usually indicates malignancy, but should be confirmed with biopsy
PET should be used to determine the extent of malignancy any time surgery or local radiation therapy is considered as the definitive treatment
The predictive or prognositic power of PET following therapy is greater than CT

54. Questions?
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