I'm Greg Kalemkerian Medical Oncologist and Professor of Medicine and Division of Hematology Oncology at the University of Michigan. This lecture will be covering lung cancer, clinical evaluation and staging. The objectives of the talk are to review the initial diagnostic and staging concepts for patients with lung cancer, and to review the staging criteria for patients with both non-small cell and small cell lung cancer. Lung cancer is a heterogeneous disease with multiple histologic subtypes and molecular phenotypes. The staging of lung cancer offers both therapeutic and prognostic guidance. Proper initial evaluation of patients is imperative for appropriate therapeutic decision-making. Our pre-lecture question is: A 63-year-old man presents with shortness of breath, cough and fatigue. CT scan shows a three centimeter right upper lobe nodule obstructing the segmental bronchus, enlarged right hilar and paratracheal lymph nodes. PET scan shows FDG-avidity in the right upper lobe nodule and in the right hilar and paratracheal lymph nodes with no distant metastases. A percutaneous biopsy of the right upper lobe nodule shows squamous cell carcinoma. What is the most appropriate further management of this patient? (A), bronchoscopic biopsy of the paratracheal lymph node (B), molecular analysis of the biopsy for driver mutations. (C), surgical resection of the right upper lobe and lymph nodes, or (D), chemotherapy plus definitive radiation therapy. Will come back to the answer to this question at the end of the lecture. So, the workup of patients with suspected cancer of any kind, not just lung cancer, can really be broken down into three important questions. What is it? Where is it? Who has it? From these three questions, we then can derive the answer to the last question which is, what can we do about it? In this lecture, we'll be talking about the first three questions and in subsequent lectures we'll be talking about the last question with regard to lung cancer. So, pertaining to what is it, it's important to figure out, number one; is it cancer or isn't a cancer. Then number two; what type of cancer is it? So, lung cancer is not just one disease. Lung cancer is a group of diseases that have some significant differences between them not only with regard to their biological behavior but also in regard to their treatment. So, most lung cancers fall into the category of non-small cell lung cancer which accounts for about 85 percent, sub-classified as adenocarcinoma, squamous cell carcinoma, or large cell carcinoma. Then there's the entity called small-cell lung cancer that accounts for about 15 percent of patients with lung cancer. This is a very distinct disease. So, adenocarcinomas are the most common subtype. They are associated with smoking as are all of these subtypes. But they are the most common subtype that is found in people who don't smoke with lung cancer. They are usually peripheral nodules and can have a variety of different growth rates from some that are very indolent and slow growing, to others that can be phenomenally aggressive in nature. The least common subtype of adenocarcinoma is the adenocarcinoma in situ, what we used to call bronchioloalveolar cancer that grows in a very slow manner in a non-invasive way along the lining of the bronchial epithelium without invasion into the submucosa or deeper tissues. Squamous cell carcinoma is the second most common subtype of non-small cell lung cancer, and is very highly smoking related with about 95 percent or higher patients being former or current smokers. This cancer usually occurs in the proximal bronchi and because of that it can cause symptoms of obstruction of the airway including cough, hemoptysis, which is coughing up of blood, or infections. It also is the most common subtype to cause cavitation of tumors which can also lead to an increased risk of bleeding. Small cell lung cancer is a very distinct disease that is decreasing in incidence as the prevalence of smoking declines. It is almost always found in smokers. I've only seen a couple of people in the last 20 to 25 years with small cell lung cancer who were never smokers. Usually presents as a central mass with involvement of mediastinal lymph nodes and as a very rapid growth rate and spreads to distant sites very early in its disease course. Because of this, about 70 percent of people with small cell lung cancer present with stage four metastatic disease, and they have a very high rate of brain metastases. Small cell lung cancer is what we call a neuroendocrine tumor. Because of this, people can develop neurologic and endocrine paraneoplastic syndromes that can have effects on their body at distance from the cancer itself. So, in addition to the histologic classifications of lung cancer, there are now a number of molecular classifications particularly of the adenocarcinomas. If we look at this pie chart, we can see that there are a number of subsets that are determined by a driver mutations such as EGFR, BRAF, ROS1 and ALK. These four driver mutations have FDA-approved therapies that target them. So, it's important to know whether or not any of those genes are deranged within a particular tumor, adenocarcinoma. There are other molecular abnormalities noted on here in yellow; MET, RET and HER2 for which we do have clinical data from K series or small studies that demonstrates potential for clinical benefit but they're not yet FDA-approved. The other subsets listed here particularly KRAS which is the most common driver mutation, we do not yet know how to target. So, what do we need to look for when we're doing molecular characterization of tumors? Well, we always can do the broad next-generation sequencing that covers 50 or 300 different genes, and that could be useful for determining research protocols and things that are a bit offline that the patient can potentially be eligible for. But in clinical practice, there really are four mutations now that need to be tested for because we have FDA-approved drugs that target them. Those are the EGFR sensitizing mutations, BRAF V600E mutation, and then the ALK and ROSI rearrangements. So, that's the basic minimum that should be tested for a standard of care in our patients. Well, who do you test? Well, we test people with adenocarcinomas and nonsmokers with non-adenoca histology. So, a squamous cell in a non-smoker should be tested as well. We only are testing stage four tumors because their at present time there's no role for molecularly targeted therapy in stages one, two, or three non-small cell lung cancer. As part of the evaluation, one can do further genomic testing with multiplex mutational analyses or next-generation sequencing, but those are primarily to identify targets for clinical trials enrollment on patients. So, moving on to the question of where is it, this gets down to staging. Staging is an evaluation of the extent and spread of the disease by knowing that we help to guide the treatment decision-making for the patient, and we also can offer general prognostic information for the patient about what the future might hold. The basic work-up for non-small cell lung cancer is a complete history and physical examination, complete blood count, and a chemistry panel that includes liver and kidney function testing. Patients should have a CT scan of the chest and upper abdomen that includes the adrenals and liver with contrast. A PET scan can be done to evaluate for lymph node involvement or for distant metastases. However, in people who already have clear cut or proven stage four lung cancer or a pet scan is really not necessary. CT scan of the brain is usually done, but except in patients who have very early stage, stage one or two operable non-small-cell lung cancer, where it is not cost effective to do brain imaging. Pulmonary function tests are important for patients who are surgical candidates to make sure they can tolerate a surgical procedure. Also, similarly, patients should be evaluated for cardiac dysfunction. For patients who have pleural effusions, a Thoracocentesis or a drainage of the pleural fluid can be very helpful because it can help define the stage of the disease by looking for cancer cells by cytology within that pleural fluid. The use of PET scan has really improved the staging of people with lung cancer. As we can see here on this slide, that when we're looking at whether or not patients have mediastinal lymph node involvement that PET scan performed significantly better than CAT scan with regard to sensitivity, specificity, positive predictive value, and negative predictive value. Importantly, when looking at the positive predictive value here, 90 percent looks like a very high value. However, 90 percent is not quite high enough to allow us to rule out a potentially curative surgical procedure. So, even if patients have positive lymph nodes by PET scan, they really need to be biopsied in order to document whether or not they actually are involved, because there are other entities that can cause pet positivity not just cancer. Things like inflammation, infection, or rheumatologic diseases can cause lymph nodes to look positive when they do not have cancer within them. So, we always have to pathologically confirm the stage of disease. So, the staging system for lung cancer is based on the stage 1, 2, 3, 4 system in the TNM classification using tumor node and metastasis as categories in order to determine the overall stage. Stage one, non-small cell is a solitary lung nodule isolated within the lung not extending outside the lung with no spread to lymph nodes or any other distance site. Stage two has a nodule in the lung plus hilar lymph node. So, lymph nodes at the root of the lung within the plural envelope. Stage three, non-small cell lung cancer generally includes patients with lymph nodes that have spread to the middle of the chest into the mediastinal, but also can include tumors that extend directly into the mediastynum or into the chest wall or into local organs. Then stage four, non-small cell lung cancer is when we have hematogenous metastasis to distant organ sites such as the brain as illustrated here. In more detail, the TNM classification scheme covers all of the different sets and subsets of stage and the new eighth edition of the AJCC staging manual has gotten much more complex as far as how do we subset the different stages and how do we distinguish the different tumor classifications with the T stage is determined by the tumor size primarily or tumor invasion, the N stage is determined by the level of lymph nodes as far as distance from the primary tumor, and then the M classifications for metastasis into either the contralateral lung or into a pleural effusions or pericardial effusions or into distant metastatic sites. I'm not going to go into more detail on this, but this you can look over and try to fully understand how this comes about. Most of the distinction in how the stages are determined is based on prognostic significance. Not necessarily therapeutic significance of the different T stages and TNM stages. So now, we get to the third question of who has it? This is really based on the characteristics of the person who presents with lung cancer. Because most people with lung cancer are smokers, they tend to have a lot of other co-morbid conditions such as emphysema, heart disease, kidney disease, peripheral vascular disease, clotting disorders, things that really can affect our ability to optimally treat their cancer. We also have to always assess a person's general functional ability something we call the performance status and for which oncologists have very discrete scales in order to measure just how functional an individual is. After stage, we know that performance status is the next strongest predictor of how well somebody is going to do with their cancer. In general, people who are doing poorly continue to do poorly whereas people who do well tend to do better. So, we use that in order to judge what treatments can patients tolerate and what the potential benefit of such treatment is going to be. Age is not by itself an absolute contraindication or reason not to do any particular type of treatment. However, it is important to understand that as people age, their reserve does decline and they do not tolerate toxicities that may arise from particular interventions as well as they would have when they were younger. In general though, functional ability is more important than age. So, an 85-year-old who isn't up and around it's probably a better candidate for aggressive treatment than a 50-year-old who is spending his entire day lying in bed. The last characteristic that's important for determining who has the cancer is the patient's own belief systems. What their philosophy of medical care is, what their acceptance of particular risks and benefits are, and how they weigh those things within their own minds. So, it's important as an oncologist to discuss with patients the options that they have and then to discuss the pros and cons of each of those options, and then to work through with the patient what they wish to do, always remembering to give them a recommendation as well in order to help them guide their own decision-making. Lung cancer is a disease that very uncommonly presents in asymptomatic people. Now with the advent of lung cancer screening, we will hopefully be finding more of these early-stage patients, but because it tends to be a disease in which most patients present with stage three or four disease, they tend to have symptoms, and we see here that the commonest symptoms being fatigue and then pulmonary symptoms which makes sense of cough and shortness of breath and then symptoms of more extensive disease such as weight loss and pain from metastatic spread. So small-cell lung cancer as I mentioned previously is a distinct disease with distinct workup and evaluation. So, lung cancer is also one of the few diseases left in which the TNM staging system is not commonly used. We should begin using the TNM system to evaluate people for lung cancer. But historically and really practically, the treatment is determined based on a two-stage VA staging system with limited-stage being confined to one hemithorax or in other words disease that can be encompassed in a tolerable radiation therapy port, and extensive disease, which is not limited disease and can involve the pleural effusions, contralateral lung nodules, lymph nodes above the clavicles, or distant metastasis. Because small cell it tends to be a more aggressive disease, two-thirds of patients at least present with extensive stage disease and metastases present at diagnosis. The work-up for small cell lung cancer also tends to be a little more aggressive. Because the frequency of asymptomatic metastases is significantly higher. The basic work-up includes a history and physical and the basic blood tests as mentioned earlier. An LDH can be obtained because this is quite a good prognostic factor for people with small cell lung cancer, indicating the burden of disease. CT scans of the chest and abdomen should be done on all patients. An MRI scan or a CT scan of the head to evaluate the brain from a testes should also be done on all patients even if they're asymptomatic neurologically. A bone scan is part of the standard work-up, but if a PET scan is done then one can exclude a bone scan. PET scans are most useful on people who appear to be limited stage by CAT scans and head scanning in order to evaluate for more distant metastases. In patients who clearly have extensive stage disease, a PET scan is unlikely to be a benefit. Bone marrow biopsies are no longer done as a routine work-up since less than five percent of people will have bone marrow disease with no other evidence of metastases, and we only do the bone marrow if there are no other metastatic sites and if patients have abnormal blood counts. So, let's look at our question that we looked at at the beginning of the lecture. 63 year-old man presents with shortness of breath and other symptoms, scan shows a right upper lobe nodule that is obstructing an airway, and enlarged hilar and mediastinal lymph nodes. PET scan shows avidity within the right upper lobe nodule and in the right hilar and paratracheal lymph nodes with no other metastases. A biopsy of the right upper lobe shows squamous cell carcinoma. What is the most appropriate step in further management? As we mentioned earlier, the most appropriate step is do a bronchoscopic endoscopically ultrasound guided biopsy of the paratracheal lymph nodes in order to confirm that they are indeed involved with the cancer. Because if they are not involved, then the patient is a surgical candidate. Whereas if they are involved, then surgery is not the best primary treatment option. So, determining the etiology of the lymph node enlargement and PET positivity is very important. Initiating treatment just based on the PET scan can lead to an adequate treatment of a patient. So, we need to first determine exactly pathologically what is and what is not involved with the disease. For squamous cell carcinomas, we generally do not perform driver mutation analysis as a standard procedure. So, the take home points for this lecture are that therapeutic decision-making requires an appropriate diagnosis, staging and patient-physician discussion of options. Staging defines the extent of disease and offers both therapeutic and prognostic guidance, and lung cancer is not one disease, there are histologic and molecular subtypes that define distinct phenotypes with differing biological behaviors and differing therapeutic options. Thank you for watching this video.