Hello. I'm Kirk Frey, the Chief of the Division of Nuclear Medicine and Molecular Imaging at the University of Michigan Health System. This lecture will be the third in a series of four, concerning the use of FDG-PET imaging in the evaluation of non-small cell lung cancer. In this lecture, we'll consider the role of FDG-PET in imaging metastatic lesions. These are my disclosures, none of which should have an influence on the topics we're discussing. So, to begin consideration of this lecture, let's pose a question that hopefully we'll be able to answer by the end of the presentation. An important contribution of FDG-PET to non-small cell lung cancer imaging is, or staging is, a, determination of primary lesion operability; b, distinction of adenocarcinoma from squamous cell carcinoma; c, negative predictive value for lesion malignancy; or d, detection of distant metastases. The learning objectives in this lecture are that participants will achieve an understanding of FDG-PET in identification of distant metastases and will understand the impact of FDG-PET in non-small cell lung cancer staging. A summary of the use of FDG-PET in a wide array of oncological settings was published in the Journal of Nuclear Medicine in 2008. A panel of experts came together and reviewed the evidence-based literature at the time, and these are the four scenarios that were reported in relevance to the imaging of lung cancer. We talked in our first lecture on the use of FDG-PET, on solitary pulmonary nodule diagnostic work, where there is evidence for clinical benefit and where the evidence quality in the published literature is considered at least of moderate quality. The staging of non-small cell lung cancer, however, was determined to be of definite clinical benefit and the evidence quality in this setting was considered high. Small cell lung cancer staging was at the time of this report considered to be of uncertain value and similarly, the use of FDG-PET to surveil for recurrence of lung cancer was considered uncertain. To understand the impact of FDG-PET on the staging of non-small cell lung cancer, it's important to understand which patients are potential candidates for surgical cure. What you see in this table are attributes of a patient's tumor and extent by primary tumor size and invasion that is T1 through T4 across the various columns. In the various rows, the lymph nodal staging, which we talked about in the prior module, as well as the presence or absence of metastatic disease that is M disease. You can see that in patients who have relatively limited size and invasion of their primary tumor, so that is a T4 as a tumor that is extensive enough that it invades critical structures within the thorax. But the fundamental distinction, T1 through T3, is the size of the primary lesion, and you can see that regardless of the size of the lesion, patients are potentially candidates for surgical cure when they have no involve lymph nodes or when they have only ipsilateral hilar lymph node involvement or intrapulmonary lymph nodes, and even patients with N2 stage disease, where nodes are seen only within the ipsilateral side of the mediastinum. N3 disease that is contralateral hilar or contralateral involvement of mediastinal nodes characterizes a patient as not surgically curable and where surgery is usually undertaken with the exception of symptom palliation in some cases. So, you can see, from this schema, that the identification of metastatic disease, this row down here at the bottom, M1, can be critical in defining a patient as not a good candidate for surgery and not at all a candidate for surgical-based cure. Some examples, this is a patient with adenocarcinoma involving multiple sites, within the left lung, within the mediastinum, probably also a supraclavicular lymph node. But notably in the abdomen and when we look at the transaxial cross-sectional images, there's a metabolically intense focus here, which corresponds to the patient's left adrenal gland. So, this patient has an adrenal metastatic lesion M1 disease, and characterizes them as not eligible for a surgical cure of their lung cancer. Adrenal lesions are not uncommon when doing whole body FDG-PET imaging. In general, we assume that metastatic lesions that are present in the adrenals have a similar FDG intensity to that seen in the primary tumor. A second characteristic of adrenal lesions considers how their activity compares to a non-involved organ. In this case, the liver, usually nearby in the same transaxial slices, can serve as an approximate point of reference. It is generally found that lesions that are less metabolically active than the normal liver are usually benign in nature. But finally, if there's an equivocal appearance, a needle biopsy may need to be performed to evaluate whether metastatic disease involves an adrenal gland or not. Here's another example of a patient with relatively extensive disease in the thorax, predominantly here on the left, but you can see at this trans-axial level in imaging the legs, that there's a focus of activity here which corresponds to a femoral bone marrow lesion which on biopsy was proven to be an adenocarcinoma metastatic deposit. It's for this reason that we recommend the PET imaging of the entire axial marrow baring space as this is where metastatic bone lesions are most likely to deposit and the staging of a patient with bone metastatic disease clearly identifies them as not a candidate for surgical cure. Finally, here's an example of a patient, where in the whole body imaging, you don't even see the primary lesion, it was a very small adenocarcinoma in the lung, but where imaging including the entire head demonstrates a focal areas of abnormality hypermetabolism within the brain, and these were biopsied and proven to be metastatic adenocarcinoma. Again, identifying the patient as ineligible for surgical cure of their lung cancer. The use of FDG-PET in staging patients with non-small cell lung cancer has been summarized in a number of trials. One of the largest is this from a multi-center Canadian study involving upwards of 300 patients who were randomized to have FDG-PET included in their staging procedure versus those who were staged by standard techniques. All of these patients had relatively limited T-stage on thoracic CT imaging to identify the presence of their tumor. Those that were staged with traditional methods underwent completion CT imaging of the abdomen and pelvis and a scintigraphic bone scan. Conversely, those who underwent PET-CT had those measures plus an FDG-PET CT scan performed. The result of the study showed that the FDG-PET CT scans were very effective and significantly more so than the routine anatomic imaging procedures in upstaging patients from the initial stage appearance in their thoracic diagnostic imaging. So you can see that correctly upstaged in the PET arm were approximately 23 patients out of 170 or so who were randomized to that arm, whereas a very small number of patients, approximately 11, were upstaged by the additional CT and bone scans. This is true if you look not only at the overall characteristics of the image-based staging, but also if you break this down by the apparent initial stage of the patient's tumor based on thoracic CT. This type of information has been repeated by other investigators, and in essence shows that probably, the major impact of FDG-PET imaging in assessment of non-small cell lung cancer is contributed by the identification of a co-metastatic disease and as a result, upstaging the patient. So let's return to our question for this lecture. An important contribution of FDG-PET in non-small cell lung cancer staging is: a, determination of primary lesion operability; b, distinction of adenocarcinoma from squamous cell carcinoma; c, negative predictive value for lesion malignancy; or d, detection of distant metastases. I think you'll all agree the detection of distant metastases is the correct answer and has very significant impact on patient management and outcome. The other answers are incorrect. Determination of the primary lesion operability, that is the T stage of the lesion, is best done with a CT or MRI and in many cases, may require actual surgical exploration in order to be definitive about this. Distinction of adenocarcinoma from squamous cell carcinoma cannot be made on the basis of metabolic intensity. As we saw in the first lecture in this series, the distinction of malignant versus benign lesions in the thorax cannot be made on the basis of FDG-PET lesion intensity. So the take home points from this lecture are, the major contribution of FDG-PET to non-small cell lung cancer staging is to the M stage or to the M category in TNM staging. Metastatic non-small cell lung cancer lesions, have an FDG activity similar to the primary lesion in the majority of instances. Thank you for your attention to this lecture, the third in a series of four, on FDG-PET imaging and its role in non-small cell lung cancer evaluation.