Using PET in Lung Cancer Place your logo here

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

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.

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.

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

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.

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

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.

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

Detection of a radiographically occult lesion 61 yr old man s/p partial colectomy for sigmoid cancer, rising CEA level to 44.8. 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

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

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

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

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

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

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

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

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

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

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):1710-1717

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

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

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

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

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.

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.

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 4238 83 91 82 64 74 68 Source: Gambhir et al, J Nucl Med 2001; 42:1S-93S

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 417 98 92 96 72 95 84 PET PPV = 93 NPV = 97 CT PPV = 97 NPV = 79 Source: Gambhir et al, J Nucl Med 2001; 42:1S-93S

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 254-261

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 102 91% 86% 75% 66% 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 254-261

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 254-261

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

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

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 41 (98% sensitivity) 3 No relapse 1 14 (NPV 93%) Total 42 17 (4 not evaluable) Source: Hicks et al, JNM 42:11, 2001 pp 1605-1613

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 1605-1613

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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