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Nasser Hanna

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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.


GRACE Video

Can Immunotherapy Play a Role in Locally Advanced NSCLC?

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GCVL_LU-FE10_Immunotherapy_Role_Locally_Advanced_NSCLC

 

Dr. Nasser Hanna, Indiana University Health, discusses the possible role of immunotherapy in locally advanced NSCLC.

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So where do we go from here? We certainly demonstrated some improvements in outcomes in the 80s and 90s and early 2000s, but we’ve sort of hit a little bit of a road block. We’ve tried a number of strategies to try to improve outcomes over chemotherapy and radiation alone. We’ve tried giving more chemotherapy before or after chemoradiation, that didn’t work out. We’ve tried escalating doses of radiation therapy, that didn’t work out. We’ve tried incorporating surgery after chemotherapy and radiation, and for a small subset of patients that seems to be effective, but for the larger group of patients that’s not really any more effective. We’ve tried empirically incorporating molecularly targeted therapy into chemotherapy and radiation and so far that hasn’t panned out. We’ve even tried to incorporate new classes of drugs, what we call antiangiogenics — these are drugs that we sometimes use in the metastatic setting and they help disrupt the blood vessels in tumors, but those proved to be either unsafe or ineffective in patients will stage III disease.

So we’ve really sort of hit a plateau a little bit on where we’ve gotten for the treatment of stage III disease. Now the newest strategies are to look at molecularly targeted therapies, but in targeted patient populations — but probably the more promising avenue of research is really in that of immunotherapy.

Immunotherapy is here, it’s a reality, it’s standard treatment for patients who have metastatic disease, and here’s the general idea: the general idea is that your immune system recognizes the presence of cancer in the body as being foreign — these cancer cells have on their surface certain proteins that the immune system recognizes as not belonging or abnormal. That’s a similar process in which the immune system recognizes viruses as foreign invaders where they recognize proteins on the surface of the virus for instance. So we’ve known for really a century that the immune system does respond to the presence of cancer in the body, and in some cases it can be helpful at suppressing cancer or killing cancer cells, but these cancer cells have developed in such a way that they’re able to resist the immune system by and large.

One of the ways that they’ve been able to resist the immune system has recently been discovered. It turns out that on the surface of cancer cells, and in particular on the surface of lung cancer cells, are certain proteins that interact with proteins on your immune cells, called T cells. When these proteins interact with one another, it’s basically like a running back with a football giving a stiff arm to a defender trying to tackle him — the defender is trying to get at it, just like the immune cell was trying to get after the cancer, but he just can’t get close enough to the cancer cell.

Well we now have a class of drugs of immunotherapy that sort of allow that T cell in your immune system to attack the cancer cell. And does it work? It’s great science, it sounds good, but does it actually work? The answer is yes, it actually works! In patients who have metastatic disease there are now drugs that work with the immune system in this manner that are able to cause a significant number of tumors to shrink. Amazingly sometimes these tumors remain regressed not just for months, but sometimes for years, and in randomized clinical trials so far it appears that in some cases the immunotherapy may be even more effective than the chemotherapy. 

That’s very good news and we’re beginning to further understand how to better take advantage of our knowledge and improve immunotherapy for patients with metastatic disease

So the natural question is, “can we take this information and incorporate it in the treatment of someone that has potentially curable disease?” That would be somebody with stage I, II or III by and large, and so these strategies are under way at this time. There are strategies that are going to be looking at giving immunotherapy after somebody has had surgery, and now there are a number of clinical trials that are testing the idea of giving immunotherapy after or during chemotherapy and radiation for those who have stage III disease. This is a prime time to give immunotherapy, but it may also be a risky time and I’ll explain that.

The reason why it may be a prime time is when your tumor gets radiated, cancer cells are dying and proteins are expressed and released from the dying tumor cells, there’s lots of inflammation, and the immune system goes into overdrive. It’s one of the reasons why when you give chemotherapy and radiation, you can get swelling on the chest wall, you can get a sore esophagus for a while, you can actually cause some inflammation in the lungs. There’s a tremendous amount of inflammation that’s occurring during this process. It’s during that period of time we believe that breaking that barrier between that viable cancer cell and the immune cell may be optimal. There are a number of clinical trials now that that are testing the idea of giving immunotherapy to these patients.

Now there is a cautionary note: we know that these immunotherapies do carry some risks — sometimes the immune system works really well against your own body’s tissues and so you can get inflammation of normal tissues with immunotherapy. For patients with stage III disease, the thing that I worry the most about is, are we going to get excessive inflammation of the esophagus which can be very painful and debilitating, and are we going to get excessive inflammation of the lungs, what we call pneumonitis? Now these side effects can oftentimes be treated by tamping down the immune system by giving steroids and in most cases that can be safely done, but there are some cases where these side effects can be extreme and I suspect there will be some cases in which these toxicities will be irreversible.

So until we fully understand how to safely do this and whether it’s effective, this type of strategy should only be done under the auspices of a carefully conducted, closely monitored clinical trial. There are those clinical trials that are ongoing right now and I think we’re going to understand the safety side of things in the next year, and in terms of the effectiveness it’s probably going to take another two, three or more years to fully understand that. But I would say as of today probably the most promising hope that the outcomes for patients with stage III disease will be better in the upcoming years does come in this area of immunotherapy.


GRACE Video

Appropriate Chemo Regimens with Radiation for Locally Advanced NSCLC

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GCVL_LU-E10_Appropriate_Chemo_Regimens_Locally_Advanced_NSCLC

 

Dr. Nasser Hanna, Indiana University Health, lists chemo regiments appropriate for use with radiation in locally advanced NSCLC.

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I’m often asked, “what is the preferred chemotherapy treatment that we should be giving to patients when combining it with radiation for those with stage III disease?” We know that for patients who have stage IV disease, we commonly give a two drug chemotherapy regimen. One of those drugs is a platinum agent, either carboplatin or cisplatin, and then the second drug really depends upon the histology or the particular subtype of lung cancer the patient has. Today, if a patient has an adenocarcinoma, that chemotherapy drug is most oftentimes going to be pemetrexed; if the patient has a squamous cell cancer, that drug oftentimes with be either paclitaxel or docetaxel, or gemcitabine.

So how do those drugs behave, or how do those drugs work in the stage III setting? Well we’ve learned some lessons: first we’ve learned that it’s very difficult to give one of those drugs, gemcitabine, in combination with radiation therapy, so as a result we’ve largely been giving paclitaxel and carboplatin. Some people use docetaxel, although most of the data is with paclitaxel. More recently, people are using pemetrexed and cisplatin, and historically we’ve used cisplatin and etoposide because in previous years that was our standard of care for patients who had metastatic disease, but really was the most well established regimen when giving radiation combined with chemotherapy in the stage III setting.

In the United States the two most commonly used regimens are cisplatin and etoposide combined with radiation, or carboplatin and paclitaxel combined with radiation. So which regimen should we preferentially give? Well those two regimens have never been compared head to head. We have looked at a number of clinical trials in which different strategies have been tested, but never the strategy of testing those two regimens head to head. Now we’ve recently gotten indirect evidence on what is the efficacy or the effectiveness of those two regimens and how would they compare if we were to do head to head comparisons, and these analyses suggest that it probably doesn’t make much difference — that the regimens are probably very, very similar. Most recently there was a clinical trial of cisplatin and pemetrexed with radiation against cisplatin and etoposide with radiation and that head to head comparison really showed no difference in outcomes between those two strategies.

Today we can say that really any one of those regimens is reasonable. Some people are wedded to the cisplatin and etoposide regimen because it’s what they’ve been most familiar with and they understand how to handle the side effects, lots of people like the convenience of carboplatin and paclitaxel  because it’s given weekly, and some people are drawn to the newest regimen which is cisplatin and pemetrexed. But I really don’t think that there are discernible differences. There may be some differences in the side effects, but I think in terms of outcomes they all seem to be fairly comparable.


GRACE Video

Is Targeted Therapy Feasible As Consolidation in Locally Advanced NSCLC?

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GCVL_LU-EA01_Targeted_Therapy_Consolidation_Locally_Advanced_NSCLC

 

Dr. Nasser Hanna, Indiana University Health, reviews efforts to utilize targeted therapies as consolidation after chemoradiation in locally advanced NSCLC.

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Because those strategies testing additional systemic therapy utilized chemotherapy and those strategies did not improve outcomes compared to concurrent chemoradiation alone, we looked to try to give other forms of systemic therapy that were not chemotherapy to see if perhaps that would improve outcomes. Beginning in the 2000s there were a number of new drugs that appeared to be active in people with lung cancer and these are what we call molecularly targeted therapies. The first of these molecularly targeted therapies targeted a certain growth receptor on the surface of cancer cells, and this is called the epidermal growth factor receptor (EGFR) and we had a drug at the time which would target cancer cells that expressed this epidermal growth factor receptor. Well we understood in the 2000s that the vast majority of people with lung cancer have tumors that overexpress these growth receptors on the surface.

So clinical trials were designed to incorporate these new molecularly targeted therapies into the backbone of therapy that we had already established. Probably the best known of these trials was conducted by one of the United States cooperative groups in which all patients with stage III unresectable non-small cell lung cancer received the standard concurrent chemotherapy and radiation therapy backbone. Now in this trial patients were allowed to receive additional chemotherapy after that but the bottom line with this trial and the importance of this trial is then at that point patients were then randomized to receive either this molecularly targeted therapy or to receive a placebo.

At the time, again, this was the most effective molecularly targeted therapy we had in lung cancer and this was our greatest hope for further advancement over just giving concurrent chemoradiation alone. This drug was called gefitinib, it is approved by the FDA today and it is commercially available for people who have metastatic disease. What this trial demonstrated was giving that drug after chemotherapy and radiation therapy did not improve outcomes. In fact more people who received placebo had long term survival compared to those who received the gefitinib. So that hypothesis was utterly rejected and clearly is not the way forward.

Since that trial was designed we’ve come to better understand which patients actually benefit from these drugs that target the epidermal growth factor receptor. In fact we have new targets including a gene called anaplastic lymphoma kinase or the ALK gene and we have molecularly targeted therapy against tumors that have that gene abnormality.

So the current state of the art clinical trials testing molecularly targeted therapy are not just indiscriminately giving everybody the drugs, but they’re testing the idea that perhaps there are subsets of patients who would preferentially benefit from these targeted therapies. So one of the United States cooperative groups right now is conducting a clinical trial for patients with stage III unresectable disease. Everyone is getting concurrent chemoradiation, but those patients who have either an abnormality in the epidermal growth factor receptor gene, or in the anaplastic lymphoma kinase gene are also being randomized to receive the molecularly targeted therapy or not.

So this is a very different idea, this is not just empirically giving everybody these molecularly targeted therapies, but it’s targeting patients for these drugs based on the molecular biology of their disease. Now these trials are ongoing right now and I think we’re optimistic and we’re hopeful because we’ve seen the activity of these targeted drugs in patients who have metastatic disease. Perhaps we’ll see some improvements in outcomes in these targeted populations — that question is probably not really going to have an answer for about two or three years. That’s the current state of the art treatment that’s being tested regarding molecularly targeted therapy in stage III cancer.


GRACE Video

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.


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