GRACE :: Lung Cancer

Imaging and Response Measurement

Lung Cancer Imaging, Debate and New Issues

What Is the Significance of Mediastinal Node Sterilization After Neoadjuvant Therapy?

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GCVL_LU-D11_Significance_Mediastinal_Node_Sterilization_After_Neoadjuvant_Therapy

 

Dr. David Harpole, Duke University Medical Center, defines the concept of mediastinal node sterilization and its use after neoadjuvant therapy.

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When we have patients who have a mediastinoscopy that’s positive, in other words we’ve found mediastinal lymph nodes that are involved with cancer, the decision comes down to what’s the best approach. Usually, when patients have what we call locally advanced lung cancer, which is lung cancer that has significantly involved those lymph nodes, that’s reserved for a concurrent chemotherapy plus radiation approach, and surgery is usually not indicated. But we do have patients whose lymph nodes were slightly involved, either with microscopic deposits or only a couple of lymph node areas that were involved, and in those patients we will give them upfront chemotherapy or chemotherapy plus radiation therapy at a moderate dose, and then reassess them after they’ve had their therapy. If their tumor has responded to the therapy, in other words on the PET scan and CT it’s smaller and the lymph nodes are less active, then we may consider a resection in those people.

The very best scenario is for patients that we do that, but then we go in and operate, that they’ve actually had their tumor completely sterilized by the therapy. I tell my patients that we use the lung mass as a measure of their response to the chemotherapy in their body, and the reason is that people don’t die from lung cancer in their chest after we operate on them, they die of lung cancer that’s out in their body and if there’s microscopic cancer out in their body, I’m not helping them by taking the lung mass out. I usually say the horses are out of the barn, and it really doesn’t care what I do to the barn, the horses are gone. If the tumor in the chest has been sterilized, there’s a very good chance that denotes that all of the tumor in their body is sterilized.

So when we resect patients who’ve had upfront treatment, if their tumor is completely dead or almost all dead from the therapy, that denotes very good outcome for the patients and they’re the ones that we have that are long-term survivors, and we do have patients that are long-term survivors after they’ve had chemotherapy plus or minus radiation and surgery.


How Do Thoracic Surgeons Assess Fitness for Surgery?

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GCVL_LU-B04_Thoracic_Surgeons_Assess_Fitness_Surgery

 

Dr. David Harpole, Duke University Medical Center, details the methods thoracic surgeons use to assess a patient’s fitness for surgery.

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One of the questions that we’re often asked is, “how do thoracic surgeons assess patients’ fitness for surgery?” Interestingly, the old technique that surgeons had before we had pulmonary function studies and so forth was just to get them and walk them up two or three flights of stairs and I still do that occasionally. If a patient’s able to walk up two or three flights of stairs they’re usually fit for a thoracic operation.

However all of our patients now will undergo pulmonary function testing to measure their lung capacity — a test called the diffusion capacity, which tests how well the lung exchanges gases. In other words, when you inhale air how well does your lung take up the oxygen from the air sacs into the blood vessels, and then how well does it release the carbon dioxide from the blood vessels back to the air sacs so you can exhale it out. That test is often the one that’s most predictive of patient’s outcome. Then if a patient has a history of any cardiac disease I will often discuss that with their cardiologist and if necessary, obtain some sort of stress testing and it’s not unusual for us, many of our patients are smokers and many of them have concomitant heart and vascular disease. I would probably say 5% of the time, my patients will have a positive stress test and end up being evaluated by cardiology for interventions before surgery sometimes.

Then we look at the stage of the cancer and if it’s an early stage cancer, we may not obtain any other tests besides routine blood chemistries and so forth. If it’s a more central cancer then we might consider getting head scans and things. I reassure my patients and tell them the likelihood of the cancer having spread to the brain is very unlikely, but we still do it to be safe. Then once that’s been obtained, we’ve gotten a PET scan to assess whether or not the tumor has spread outside the chest. Then we can sit down and discuss what type of operation will be undertaken. For a simple resection or lobectomy that’s usually it; if it’s something that requires more then we may require other testings to measure the impact of the surgery on the patient. If one is taking the entire lung out, that’s certainly a larger operation than taking part of a lung out and so I’ll discuss that with a patient and the possible changes in their lifestyle that may occur with a pneumonectomy, which is the term for removing the whole lung, if that’s required, so that they can fully understand and be fully informed about what they may undergo in the near future.


Is There a Role for PCI in Locally Advanced NSCLC?

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GCVL_LU-E10d_Role_PCI_Locally_Advanced_NSCLC

 

Dr. Nasser Hanna, Indiana University Health, addresses the issue of prophylactic cranial irradiation (PCI) in locally advanced NSCLC.

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Unfortunately many people with stage III disease are not cured of their cancer. We’re doing better, but we’re not doing good enough for most people and for those people who are not being cured, oftentimes the cancer will recur in what we call “distant sites.” That may be bones, it may be the liver, it may be the adrenal glands, these two small glands that sit above the kidneys, and sometimes it can be the brain.

When cancer progresses and shows up in the liver or shows up in the adrenal gland, it can certainly be disconcerting, sometimes it can cause symptoms and people don’t feel well, but oftentimes it’s something we just see radiographically. That’s oftentimes not true when cancer recurs in the brain. When it recurs in the brain, oftentimes it’s very unpleasant for somebody. They may have headaches, they may have double vision, they may have unsteadiness or nausea, they may pass out, they may even have seizure activity. So the idea of trying to prevent cancer from spreading to the brain is of paramount importance.

Now in another type of lung cancer, small cell lung cancer, we have utilized a strategy of prophylactically radiating the brain because we know that so many patients with small cell lung cancer eventually develop cancer in the brain. Prophylactically radiating the brain before any signs of cancer have appeared there may do one of two things. Number one is there actually may be microscopic disease in the brain that we really can’t detect on imaging studies for which you’re radiating when you’re doing the so-called prophylactic brain radiation. Secondly, some people believe that when you radiate the brain, it forms sort of an inhospitable environment for cancer to subsequently implant and seed. Either way, we’ve demonstrated that in patients with small cell lung cancer, you can reduce the incidence of brain metastases and in some cases actually help people live longer if you prophylactically radiate the brain.

Now the incidence of brain metastases in those with stage III non-small cell lung cancer is not as high as those with small cell lung cancer. Having said that, about 30-35% of those with stage III disease do eventually develop brain metastases. So the question has come up: should we or could we prophylactically radiate the brain and achieve fewer brain recurrences and perhaps maybe even help people live longer or cure more disease? Well the answer to this question is really unknown — there was one attempt at a carefully conducted clinical trial to test this idea, and unfortunately it was very difficult to accrue to this clinical trial, and it ended up only accruing about a third of the patients that it was meant to accrue.

We got some limited information from this clinical trial and what we learned is yes, we can reduce the incidence of cancer appearing in the brain by prophylactically radiating it. We really weren’t able to demonstrate in this small group of patients an ability to cure more people or help more people live longer, and certainly prophylactically radiating the brain does come with some side effects such as hair loss, fatigue, sometimes headaches, and sometimes nausea.

As of today, it is not standard to prophylactically radiate the brain in patients with non-small cell lung cancer and I’m not sure we’re ever going to get the completion of a clinical trial that will adequately address that, so I suspect for now and probably forever that will not be a standard approach for patients with stage III disease.


Is There a Role for Induction or Consolidation Chemotherapy Before/After Chemo/Radiation?

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GCVL_LU-E10c_Induction_Consolidation_Chemotherapy_Role

 

Dr. Nasser Hanna, Indiana University Health, considers the use of induction or consolidation chemotherapy for unresectable stage III NSCLC.

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Can we do better than what we demonstrated in the 90s and early 2000s with concurrent chemoradiation? We know that we improved outcomes, that people were having more tumor shrinkage and control of their tumors was a little bit better. We were actually even able to cure more patients but we still were not curing enough patients. These were modest gains and they came at the consequence of having a number of side effects.

So we hypothesized that perhaps patients just needed more systemic therapy. The major reason for death from lung cancer is systemic recurrences, and so while we were doing pretty good with radiation and in some cases surgery, patients still had poor control over the disease over time because it would pop up in the liver, or in the brain, or in the bones, or elsewhere.

So throughout the 2000s there were two basic strategies that were tested. One strategy was to give a couple of courses of chemotherapy first, and then give patients chemotherapy and radiation concurrently. The other approach was to give chemotherapy and radiation concurrently from the get-go, but when folks were done with treatment, give them additional chemotherapy.

Both of these strategies were studied in multiple groups on multiple continents over about a five to ten year period of time. Unfortunately the bottom line to all of this type of treatment is that neither giving chemotherapy first, prior to concurrent chemoradiation, nor giving chemotherapy after concurrent chemoradiation was able to cure more people than simply giving chemotherapy and radiation at the same time.

So while we have tested a number of drugs in a number of different strategies, the bottom line is we’ve never been able to demonstrate further improvement in outcomes compared to just giving chemotherapy and radiation concurrently, alone.


Local Therapy for Limited Acquired Resistance

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GCVL_LU-FB06_Local_Therapy_Limited_Acquired_Resistance

 

Dr. Jared Weiss, UNC Lineberger Comprehensive Cancer Center, describes the types of situations in which local therapy is appropriate for treating limited acquired resistance.

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It’s my privilege to speak to you today about a favorite topic of mine, local therapy for limited acquired resistance.

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So just five years ago, we were celebrating the curves that I’m showing you here. This is great — we have a targeted therapy, it works better than chemotherapy, it’s less toxic, it’s more convenient, demedicalizes the patient’s life, and this is a legitimate victory and I don’t want to take that celebration away, but I think only five years later, I guess now six years later, I think the perspective is a little bit different as our drugs get more effective and the bar goes up.

GCVL_LU-FB06_Local_Therapy_Limited_AR_03 

We say these drugs are lasting less than a year on average — now what? We’re trying to find something other than chemotherapy. There are multiple promising approaches, including next generation drugs aimed at the targeted therapy, but I’m going to talk to you today about a slightly different approach. Before doing so, I want to just share that this story is very analogous for crizotinib and ALK and ROS1, it’s the exact same story.

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The approach I colloquially call “weeding the garden.”  This approach is what it sounds like — using some kind of local ablation or surgery to take out areas of progression, areas that are growing despite the targeted therapy, the areas that perhaps have a resistance mutation of some kind, and then using the original therapy for the rest of the cancer that’s still well controlled.

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So when might this make sense, and when might it not? Well the situation  where it surely does not make sense is classical progression. Prior to the advent of targeted therapies and immunotherapies, there was really only one pattern of progression that we mostly saw: when the cancer was going to grow, it grew everywhere and it grew in multiple new spots — not a time when weeding the garden makes good common sense.

We have two new patterns of progression where it does make more common sense. One is oligoprogression — that is what it sounds like, you have progression in just one or two spots, those spots maybe have T790m or some other resistance change, where the rest of the cancer is beautifully controlled still on the targeted therapy. The other situation is when the progression is in an area that the drug doesn’t get to so well. So there’s this filter between the rest of the body and the brain called the blood-brain barrier. Its job is to keep poisons out of the brain and it appropriately sees most of our anti-cancer therapies as poisons and keeps them out of the brain. You can have cancer growing in the brain not because there’s some resistance gene, some secondary mutation or amplification of some gene, but just because the drugs aren’t getting there well. I think that’s another area where it conceptually makes sense to consider weeding the garden.

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For EGFR, I think radiation is a particularly promising approach to do this — at left you can see data preclinically in the lab on why EGFR mutated cells seem to be more sensitive to radiation than non-mutated cells, and at right some human data to back up that this actually happens in real people.

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This approach has been tried retrospectively — the Memorial group here did a mostly surgical series where they got a median time until progression of another ten months after this approach, so they’ve mostly cut out the sites of progression and started TKI back up again.

GCVL_LU-FB06_Local_Therapy_Limited_AR_08 

Our colleagues at Colorado, where we happen to be taping today, have done this in a mixed series of EGFR and ALK patients; they show their data separately for whether the progression was primarily in the brain or elsewhere. When the brain was the primary site of progression, they got another 7.1 months out of targeted therapy. When it was outside of the brain, they got an additional four months.

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I have the privilege to lead a study prospectively evaluating this approach for patients with oligoprogression on EGFR mutation. The design is very simple, you have to have gotten benefit out of an EGFR TKI, typically erlotinib in the first line in this country, but no prohibition against gefitinib or afatinib, but now one or two sites, up to five sites, are growing. We do stereotactic radiosurgery to those sites of progression, and then restart a TKI for the remainder of the sensitive disease. My collaborators are shown at right, including many GRACE contributors.

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[In 2015] Pfizer agreed to fund a very similar study for patients who have previously received a benefit on crizotinib but are now  progressing. The design is rather similar here, where we do radiosurgery to the sites of progression, restart the crizotinib, and because which mutations are sensitive to crizotinib is evolving at the current time, we don’t define this on a molecular basis but on a practical basis — patients who have received benefit but now have growth in four or less spots.

You might reasonably ask me the question, “well we have all these exciting next generation tyrosine kinase inhibitors we’ve heard about on GRACE, we have the clovis compound and the AZ compound for EGFR, we have alectinib and ceritinib for ALK — why not just jump to one of those?” I actually think that would be a perfectly reasonable approach, perhaps the preferred approach when there’s poly progression, but I can show you graphically why you might consider the approach that I’m talking about.

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So here’s the approach of starting with the first-gen TKI and moving straight to the next-gen TKI. Let’s imagine that my approach of eliminating oligoprogressive disease only has minimal efficacy, only gets you a few extra months on the first line therapy, you might look at this graphically this way: that you’ve inserted an additional therapy, you’ve squeezed a little more juice from the orange, in first line, before moving to that next line. But it’s entirely possible that in reality we get something better than that. So the first of these alternative hypotheses is that we get a longer duration of control — perhaps ten months or a year, replicating the original experience with the first line targeted therapy. Here we have a larger advantage to total cancer control before moving on to chemotherapy. Alternatively, if we’re radiating spots, we may be eliminating some of the spots that are eventually going to cause resistance on second line TKI, and so it’s entirely possible, I would call it my professional fantasy, that we’ll actually not only prolong the duration of benefit of the first line drug, but make the second line drug last longer when we get there. The possibility of that approach is shown at the very bottom — that fantasy phenomenon.

So I thank you for your kind attention.


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