Let me swing this to you guys. Today, I got called by a colleague who had what they thought was early-stage cancer. I hadn’t seen the patient yet, he was asking me if I could help. When they got to surgery, he said [there was] a tiny amount, I guess a microscopic amount of disease, and an N2 node, and that’s it. Technically it was a stage III cancer at the time of surgery. He was asking what more we should do. I told him I didn’t think there was an indication for radiation, and we talked about the benefits of adjuvant chemotherapy. I said, “Are you going to ask me about EGFR?” He goes, “I’ve got one better for you. The patient came back with a 

This comes up [sometimes]. In stage IV cancer, we know very well that there are 7 other targets besides EGFR that we have therapies for. It’s important for this session that we’re doing with potentially a global audience here that there’s no indication for any adjuvant TKI [tyrosine kinase inhibitor] use outside of EGFR at this point. We’re waiting for additional information from ongoing cooperative group adjuvant studies to know what to do for other alterations, like 

I’ll throw it back to you guys. Dr Singh, in this case, the patient’s EGFR status was unknown. What are you doing when I call you up and say we didn’t get enough tissue, or for whatever reason EGFR status wasn’t tested? How do you usually respond to that or address that?

If it makes a difference to your treatment options, obviously I don’t offer that treatment myself in my discipline, but if that was something you needed, we’re here to serve. That’s what the pulmonologists do basically. We say, “We can get this to you.” If we can get enough information to you safely and expediently, then I think we will likely try to help you as quickly as possible.

David, do you know if your team runs it on the biopsy that Dr Singh [would do]? Or do you wait and just do it on the specimen you take out?

It depends on what we’re thinking about. For an isolated lesion like this, we probably would only do it on the latter. For anything more than this, as Dr Singh pointed out, where we’re looking at other levels, invasive stages and stuff, we very likely may run the EGFR. We often do that as a single mutation panel just for that 1 test right now, and we’re doing it up front from a biopsy, as opposed to some sort of next-generation sequencing group. But I think this is changing and evolving very rapidly.

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A panel of distinguished experts discuss how detection of actionable mutations affect their treatment choices in non-small cell lung cancer.

Therapies Targeting Specific Molecular Alterations in NSCLC

Let’s talk about what we’re dealing with here. We have stage I adenocarcinoma. The surgical outcomes look good, it was a lobectomy, the margins [and nodes] were negative, and there were no other high-risk features. We presume the patient had a great recovery and there were no other suspicious findings. As we all know, in real life, the PET [positron emission tomography]–CT scan isn’t exactly perfect. There are always some other nodules or something else you’re trying to figure out if it is connected or not. So the patient comes in to see [one of us] and is saying, “What else do I need to do?” Dr Singh, maybe you don’t have adjuvant discussions, and you leave that to your radiation medical oncology colleagues, but it is your sense that this patient is done, or [do they] need other therapy?

There’s some variability here. Obviously, there are some data to suggest they might benefit from additional therapy, but for now, I think we’re still trying to figure this out. I think it’s an individualized discussion at this point. The fortunate part, which you mentioned earlier, [is that] the bronchoscopy now can get you enough tissue for molecular testing. We try to give that option. Should that patient opt to proceed with something systemic, I think we’ll have that option for them. I think the word is still out though. There are some data to suggest that this patient may be done, but there are some patients, high-risk patients for example, for whom the medical oncology community may say, “This patient really wants to try something additional.” I think we can get into that, and there’s a suggestion of some data to support that. But again, it’s an individual decision, and I don’t think there’s a universal solution quite yet.

I think that’s fair. In some parts of the world, in Southeast Asian countries, there are some adjuvant recommendations for a 5-FU [5-fluorouracil]–based regimen in stage I cancer. In the United States, that has not really been adopted. In general, for smaller stage I cancers, we generally don’t recommend chemotherapy, although we have that conversation. The latest question that comes up is, is there a role for immune therapy or targeted therapy? Let’s start with EGFR because these are the more relevant things to discuss. David, to swing it back to you, are you getting 

 mutation testing done on every patient you operate on regardless of anything else?

This particular case is an under-3-cm tumor with no high-risk features. I think most of us would not recommend adjuvant therapy, except on [a clinical] trial, for this patient. We are getting pretty much reflex testing of all of our resected patients. But if [a patient] is at a smaller center, for less than 3-cm lesions, it’s probably not unreasonable to hold back on that. I think all the information we can gain is important. God forbid, if this patient recurs, it would be nice to have had that information beforehand to help you, David, if you’re looking at a recurrence situation and what to do for next therapy.

Yes, I think that’s well said. I’ll reference for our viewers [that] what Dr Harpole is alluding to is the ADAURA study. This is a trial that was trying to define the role of adjuvant EGFR TKI [tyrosine kinase inhibitor] therapy, osimertinib, in patients with 

mutations. To run through things quickly, this study took patients with stage I through stage III disease, but everybody had an 

 mutation. Patients would get chemotherapy or not, according to their doctor’s preference. It was a global study, and so there were a lot of patients with stage III cancer who didn’t get adjuvant chemotherapy. Everybody was randomized to osimertinib or not. The trial had a disease-free survival [DFS] end point, and you stayed on osimertinib for 3 years.

The trial demonstrated a DFS advantage in favor of osimertinib, and osimertinib was FDA approved in the United States for adjuvant use, but there are a couple of caveats. No. 1 is we’re waiting on overall survival data. No. 2, remember that chemotherapy was optional. The FDA approval was really for stage II and stage IIIA disease. If you go to the 

 paper and you go to the appendix, there’s a nice graph of the different stages and the DFS for each of those stages [of cancer], even though for the overall intent-to-treat [population], the primary end point was in stage II and stage III. There is an advantage that is demonstrated for stage I cancers for osimertinib vs not, but not powered enough to be in the intent to treat—it was not a primary end point, so it was a secondary end point mixed in with all the other stage II and stage III patients.

So, what to do? For patients in front of you in the office, the textbook technical answer is there’s no indication for adjuvant osimertinib in stage I cancer. However, I still have the conversation with the patient. I let them know what the trial showed and didn’t show, and what the FDA approved. I’ve had some patients say they want to do it. I’ve had a couple pursue it, and of course, I helped them pursue that, and we were able to get it. It’s outside the label, it’s not indicated, but if you have a conversation with the patient, [it may be] still what they want to do.

David Spigel, MD, and David H. Harpole Jr, MD, describe when adjuvant therapy is recommended in early stage NSCLC and discuss data from recent clinical trials of adjuvant therapy.

Adjuvant Therapy in Early Stage NSCLC

Recently I saw a woman with—very much like this case—a stage IA cancer that was resected. It was [performed by a] surgeon in town I don’t work with that much. I noticed the patient had a wedge resection. The patient came to see me and said, “What else do I need to do?” As we’ll talk about in that case, there was no indication for PD-L1, EGFR, or chemotherapy. But I couldn’t shake it, part of me was thinking, “You didn’t really have the ideal surgery.” What are your thoughts about, maybe not that case, but am I wrong [that] we’re still aiming for lobectomies? I guess the better way to ask this question is, when is a wedge good enough?

There have been 2 really important studies that came out in the last 12 months. One was the JCOG0802 study, which randomized 1100 patients to lobectomy or segmentectomy. Those were 2-cm or smaller adenocarcinomas. That revealed a slight improvement, interestingly, in overall survival for the segmentectomy, but a higher local recurrence rate. Then [there was] the CALGB 140503/Alliance trial, [Nasser] Altorki’s, [MD,] trial, which was segmentectomy or wedge vs lobectomy on around 900 patients, which showed equivalency.

I always bring out the key point that in the Altorki trial, which we put a number of patients on, the patient had to have a diagnosis of cancer, but more importantly had to have all nodal stations sampled in the operating room and found to be negative prior to randomization, which was not the case for the Japanese trial, where they had some node-positive patients. It makes it confusing, but right now, we don’t ever believe a wedge should be primary therapy in a good-risk patient. If one is going to entertain that idea, they certainly need to do a full nodal staging with that to get the answer.

I apologize, I’ve not always equated wedge with segmentectomy. I thought segmentectomy was even a little more, am I right?

The segmentectomy is what we and thoracic surgical oncologists prefer because when you do the segment, you dissect down into the segmental bronchi. So by definition you get the 11, 12, and 13 nodes, but more importantly, it’s an anatomic resection where you take the artery, vein, and bronchus together, whereas a wedge is just basically taking a chunk out. So we really do favor segments.

Yes. It’s frustrating when you’re seeing somebody with such good outcomes. You don’t want to disparage your colleagues in the community, but it struck me that that wasn’t the appropriate surgery for that patient.

There’s that very depressing SEER [Surveillance, Epidemiology, and End Results] data set, which looked at patients who had either lobectomy or wedge, and then just stratified by number of nodes taken, and there was a dramatic difference in 5-year survival. It’s clearly stage migration. In other words, the ones who were really staged with nodes did much better than those who weren’t. When you have someone with a wedge with no nodes, you really don’t know what stage they are, and it makes it more difficult for you to figure out therapy.

Yes. Fortunately, she had all the nodes sampled that we needed.

A panel of experts in the treatment of NSCLC discusses how they manage patients with stage IB disease.

Treatment Approach for Patients With Stage IB Disease

David, I’m curious. When I started almost 20 years ago out of training, I remember the surgeons I worked with and they were great. Their advice was, if it’s a solitary lesion, just take it out, don’t even bother biopsying it. Of course, back then we were just learning how to do PET [positron emission tomography] scans. [Discuss] your thoughts on how a patient who comes to you at Duke [University Medical Center] approaches with a solitary lesion. What are you doing? Are you doing a PET scan? If I’m not mistaken, I think you do your own scopes, but could you expand on your approach to the workup of a solitary lesion?

It has certainly evolved, and frankly, most rapidly over the last 2 to 4 years. As this wave is moving across the country and things are changing, I will tell you, we were a universal mediastinoscopy center for everyone. I used to do literally 300 or 400 a year, and now I do like 15…. I think the EVIS EXERA III platform that we use, and interventional pulmonary uses, has supplanted that. I will say that with the robotic platforms now, I think that has been our primary [procedure] as well. The reason being is that historically, [with] a 2-cm lesion like this that’s suspicious, we would’ve just taken it out without a diagnosis. We can go more into about the size and what we find, but certainly lesions greater than 3 cm where there are some other options now, we have been getting not only cytology but histology and molecular information on them, and we’re going to obviously discuss that more.

This [case] is pretty much a straightforward T1 lesion that I would say probably half of the thoracic surgeons now would take out without a diagnosis. We tend to get a diagnosis now more than we used to, and I think it has killed 2 birds with 1 stone because with EVIS EXERA III and our navigational [bronchoscopy], we can get a tissue diagnosis of the lesion as well as the nodal stations at the same time. This is truly a team [effort], and I think our interventional pulmonary team has become even more important to that.

David H. Harpole Jr, MD, a thoracic surgeon, details his workup approach and discussed molecular testing for patients who present with NSCLC.

Workup and Molecular Testing for a Patient with NSCLC

We’ll start with the first case. Let me walk you both through this. This is a 57-year-old woman who’s a nonsmoker, which is probably not [the majority of the patients] for the 3 of us who operate in a tobacco region in the Carolinas and Tennessee. This patient was found to have ground-glass opacity in the right upper lobe in 2016. Five years later, this imaging showed presence of a dense, nearly 3-cm lesion, so not just a wispy abnormality, but a defined lesion in the right upper lobe. Bronchoscopy revealed adenocarcinoma. Further imaging included a PET [positron emission tomography]–CT [computed tomography] scan, which did not show any evidence of distant disease. This patient underwent a right upper lobectomy, which again revealed adenocarcinoma with negative margins, but also negative nodal involvement. There were no other signs of maybe a more aggressive cancer, no LVI, lymphovascular invasion, or visceral pleural involvement. The EGFR status was unknown.

Dr Singh, I’ll start with you on some basic things to talk about. When I meet patients perhaps not from my system, and I see they’ve had a bronchoscopy, I always wonder whether it’s like what happens at our center, where we do navigational bronchoscopy and are able to get really good samples of tumors? Talk a bit about your approach to the different technologies and working [patients] up. At least at my center, we’ve shifted away from our surgeons in terms of [them] getting us tissue and a diagnosis. We’re looking for our pulmonologist to do that. But Dr Singh, talk about how you approach that initial evaluation.

Thanks, Dr Spigel, for teeing me up with that good question. There is a lot of variability obviously. This is a huge issue in our country right now to figure out, the variability is almost astronomical. This can start in many different ways, depending on the community that you’re in. I’m part of a large health system. I used to say that my job was actually medical director of pulmonary oncology quality. We struggle with this, because I work at a center that has a lot of bells and whistles. I have navigational [bronchoscopy], but I also have robotic-assisted navigational bronchoscopy. It’s the frontier now for the entire lung. Minimally invasive biopsy is potentially at our doorstep. It’s great, but it’s not the reality in many centers. People who might be in the audience, for example, may not have access to these things.

Through robotic bronchoscopy—I did a few today, for example—we can do all kinds of biopsies for cytology alone, but also for these types of ground-glass opacities. This [patient’s lesion is] dense, but you can use a variety of different tissue tools to acquire that lesion, anything from needles to forceps, now even with a cryoprobe where you get larger pieces of tissue. So tissue volume, histologic architecture, immunostaining, and molecular testing for minimally invasive biopsies is well within reach through bronchoscopy in many centers, and it’s expanding.

That being said, many places don’t have that. So then you have to start thinking, what can I do to accomplish my goals? This situation is potentially a stage I disease. We have to figure out, do we need to do a minimally invasive biopsy, or do we trust the other aspects of PET-CT? That’s going to vary from place to place. This is where we have a bit of variability, and we’re still learning in the space. It’s also institutional preference or surgical preference, if a surgeon wants a biopsy vs they don’t need a biopsy. If all roads lead to resection, do you really need to have a biopsy? These are things we’re still struggling with. Just because we can, should we?

Now, this lesion is borderline, up to the point where in our center and with the guidelines, at 3 cm in 1 dimension, we probably should do invasive staging of the mediastinal preoperatively. That’s where in bronchoscopy, that 3-cm mark from a system perspective is our hard stop. You might say it’s our quality metric. At that point, 3 cm is where we educate our oncology community to say, we need to at least consider invasive mediastinal nodal staging if we can, if it can’t be done surgically. For patients who are nonsurgical candidates, hilar node staging [should be done] as well, to make sure that our radiation oncology colleagues can obtain the information they need to proceed. And with bronchoscopy, nodal staging is extremely low risk in skilled hands, so that’s a nice dimension to have. The further you get out with the lesion, the harder they are, but we’re getting to very tough areas where we successfully biopsied areas that traditionally had not been accessible to the pulmonology community.

Thanks. [Those are] so many great points.

David Spigel, MD, presents a patient case of a 57-year-old woman with NSCLC, and Jaspal Singh, MD, MHS, discusses his approach to initial evaluation.

Patient Profile 1: A 57-Year-Old Woman Diagnosed With NSCLC

Hello, I’m Dr David Spigel, a thoracic medical oncologist and the chief scientific officer at Sarah Cannon Research Institute in Nashville, Tennessee. It is my privilege to be joined by 2 great colleagues to discuss recent advances in the management of early stage non–small cell lung cancer. There’s been a lot going on, certainly a lot of breakthroughs in the last year that involve not just medical oncology obviously, but surgical and radiation oncology as well.

We have some cases we’re going to go through over the next 45 minutes or so that I hope highlight some of these recent advances, but maybe even more importantly, some of the challenges we still face as these new breakthroughs come into play and how we incorporate this into standards of care, and of course, what the next big questions will be. Before we dive into the cases, I’ll start with some introductions of my colleagues and let them introduce themselves. We’ll start with Dr Singh.

Hi. Thank you so much. I’m Dr Jaspal Singh. I’m a pulmonologist in Charlotte, North Carolina, at Atrium Health and Levine Cancer Institute. I’m a clinical professor at Wake Forest School of Medicine, where I’m a pulmonologist. My job is to tee people up for the rest of the oncology team to move quickly, expeditiously, and safely with the best chances for cures.

Hi, I am Dr David Harpole. I’m a professor of surgery and pathology at Duke [University Medical Center, Durham, North Carolina] and one of the directors of our thoracic oncology program.

Great. Thanks, Dr Harpole. I’ve had the chance to do several multidisciplinary education events with Dr Harpole. I think, Dr Singh, you and I may have worked together before too, but I look forward to this conversation. I would bet our conversation over the next 40 minutes or so is not unlike what happens for the 3 of us every day. In my case, I’m on the phone or texting my interventional pulmonology colleagues and radiation and surgical oncology colleagues almost every day about patient care. I’m sure that’s the same for you when you interact with your medical oncology colleagues. I think lung cancer always has been the best example of multidisciplinary care in terms of how you incorporate new advances as they occur.

I thought it might be best if we do these cases together, not just reserve it for pulmonary or surgery, and we’ll demonstrate how each of the disciplines gets involved in care. We have a couple of cases here. [There may even be] time to discuss some other things that come up.

A panel of experts introduce themselves and explain their approaches to multidisciplinary care in treating non-small cell lung cancer.

David H. Harpole Jr, MD

Articles

Therapies Targeting Specific Molecular Alterations in NSCLC

Adjuvant Therapy in Early Stage NSCLC

Treatment Approach for Patients With Stage IB Disease

Workup and Molecular Testing for a Patient with NSCLC

Patient Profile 1: A 57-Year-Old Woman Diagnosed With NSCLC

Multidisciplinary Care in Non-Small Cell Lung Cancer