GRACE :: Lung Cancer

Search cancerGRACE.org

Radiation therapy

Radiation therapy options and emerging techniques

GRACE Video

CNS Disease in ALK-Positive NSCLC: Monitoring and Systemic vs. Radiation Therapy

Share
GRACE Cancer Video Library - Lung

GCVL_LU-FC05_CNS_Disease_ALK-Positive_NSCLC_Monitoring_Systemic_Radiation_Therapy

 

Dr. Ross Camidge, University of Colorado, discusses management of CNS progression for ALK-positive NSCLC including monitoring frequency and preferences between systemic and radiation therapy.

Download Transcript

How Did You Like This Video?

Please feel free to offer comments and raise questions in our Discussion Forums.

 

Transcript

As we started to treat ALK-positive patients with crizotinib, it became clear that the brain was somewhat of an Achilles heel. It was a common site for people, when their cancer started to grow, for that to be the site where their cancer was growing, and we know that in many of those cases that’s the only site where the cancer is growing. We know from a small number of studies where people have actually sampled blood levels and from the fluid around the brain that actually very little of the crizotinib is getting in, so it’s maybe just that you have a relatively under-treated part of you.

Now that plus the fact that people fortunately live a long time with ALK-positive lung cancer means that the brain can become this area that will crop up with disease. For me that means you should absolutely keep an eye on the brain. If you have no known disease in the brain I would do an MRI scan at least every six months. If you do have known disease in the brain, even if it’s treated, I would be looking more frequently, possibly as frequently as one scanning the body on treatment, or maybe half as often.

Now if you do have disease in the brain, because the activity of crizotinib is not zero, unless you have a lot of symptoms from the disease in your brain, many people will start on the crizotinib, but obviously keeping a close eye because if you do progress in the brain, then you may have to salvage it.

You can salvage it in a number of different ways. One would tend to stay on the crizotinib and either have local radiotherapy or occasionally surgery depending on the site of the deposits in the brain. For me though, there’s a difference between one type of radiotherapy and another. For example, you can either treat the whole brain, what’s called whole brain radiotherapy, or you can treat individual lesions with what’s called stereotactic radiosurgery or SRS. I very much prefer giving SRS, even to a reasonably large number of lesions, than whole brain radiotherapy for the simple reason that people with ALK-positive disease are now living long enough that they’re manifesting the side effects of whole brain radiotherapy and that can mean word finding difficulties, memory difficulties.

So I think for me if you’re just at the point where you can spot weld a few areas with stereotactic radiosurgery, that’s fine — stay on the crizotinib. But if someone is thinking about whole brain radiotherapy, I would probably switch to a next generation ALK inhibitor rather than do the whole brain radiotherapy because we know they have good activity in the brain.


GRACE Video

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

Share
GRACE Cancer Video Library - Lung

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.

[]

Download Transcript

How Did You Like This Video?

Please feel free to offer comments and raise questions in our Discussion Forums.

 

Transcript

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.


GRACE Video

Is There a Role for PCI in Locally Advanced NSCLC?

Share
GRACE Cancer Video Library - Lung

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.

Download Transcript

How Did You Like This Video?

Please feel free to offer comments and raise questions in our Discussion Forums.

 

Transcript

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

Chemoradiation as a Standard of Care for Unresectable NSCLC

Share
GRACE Cancer Video Library - Lung

GCVL_LU-E09_Chemoradiation_Standard_Care_Unresectable_NSCLC

 

Dr. Nasser Hanna, Indiana University Health, discusses the development of chemoradiation as a standard of care for unresectable stage III NSCLC.

Download Transcript

How Did You Like This Video?

Please feel free to offer comments and raise questions in our Discussion Forums.

 

Transcript

So what is the standard of care treatment for those who are not going to have surgery for stage III disease that are either medically inoperable or they are surgically unresectable? Well for decades radiation therapy has formed the backbone of treatment. If you can’t surgically remove a tumor, you can certainly apply radiation to that tumor; you radiate the tumor, the lymph nodes, and some surrounding tissue where microscopic disease may be. That form of therapy can be effective but by itself oftentimes is not curative. It will shrink tumors and oftentimes patients will have a reduction in symptoms, maybe a tumor was compressing an airway or maybe it was causing them to cough up blood or something like that where the radiation therapy can be effective at relieving some of those symptoms.

Historically radiation therapy alone for stage III disease has resulted in about a 5% cure rate — the vast majority of patients will develop growth shortly thereafter, either outside the radiated field, occasionally in the radiated field, but most commonly distant metastatic disease. That’s because even though the disease appears to be confined to the chest, we know that the majority of patients already have microscopic spread of their cancer to other parts of their body. That’s not something that you can see on a CT scan, it’s not something that you can see on a PET scan, it’s certainly not something you can feel on a physical exam, but we know that’s the case because historically when you’ve done surgery alone for this group of patients and successfully removed all the disease you can see, the vast majority of people will still develop distant, recurrent disease usually within about a year’s time. Radiation therapy alone can have some effectiveness for patients, but by and large it’s a short term effect and it oftentimes doesn’t cure patients.

Starting really about three or four decades ago, chemotherapy was beginning to be incorporated in the treatment of patients with stage III disease. In the 1970s it was demonstrated that chemotherapy could shrink cancers that had already metastasized, and perhaps if it could shrink cancers that were large enough to see on x-rays, maybe it would be effective enough to treat that microscopic disease that patients have with stage III lung cancer.

So beginning in the 1970s and really going in full force in the 1980s, chemotherapy was incorporated with radiation strategies and a whole host of different strategies were tried. The most common strategy was to give a couple of courses of chemotherapy first, try to shrink the cancer, try to treat that microscopic metastatic disease early on, and then follow that with radiation therapy. Early efforts into that approach were not terribly successful, and that’s for several reasons. Number one, our staging tools weren’t very good, so oftentimes even though we thought patients have stage III disease, they oftentimes already had stage IV disease and they weren’t going to be cured with that type of strategy. Secondly, many patients who participated in those clinical trials were already not doing well. They had what we call a low performance status, in other words, they had already become very debilitated by their disease and their ability to tolerate therapy wasn’t very good. Thirdly, our radiation techniques were fairly crude at the time, radiation planning was very crude at the time as well. Fourth, our chemotherapy actually was not terribly active; although it was modestly active, it probably wasn’t the most effective therapy that patients could receive. Lastly, it really wasn’t recognized, the clinical significance of having weight loss. So oftentimes patients will have suffered a lot of weight loss which is really a signal that they truly have systemic disease, and when you include all those types of patients on clinical trials, you’re really setting yourself up for failure.

The initial attempts at trying to treat patients with both chemotherapy and radiation therapy really would be considered failures. Outcomes were not very good, we really didn’t seem to improve cure rates over radiation therapy alone, and this was in an era in which chemotherapy was not very well tolerated. That really started to change in the mid-1980s, and really a landmark trial was conducted by a United States cooperative group. In this trial, patients were excluded if they had a really poor functional status, if they had significant weight loss, and so it really narrowed the group of patients who could potentially benefit from this therapy. In this study, patients received two courses of chemotherapy, and then that was followed by six weeks of radiation therapy. For the first time, we were able to demonstrate an improvement in cure rates. It was fairly modest, we went from about a 5% cure rate to about a 15% cure rate.

Because that was the first time that was really ever demonstrated, a second trial was required to really make sure that this was a real finding. So a second trial was done in the United States by other cooperative groups; this was a much larger trial and they essentially replicated that data.

Well in the 1980s and in the 1990s, this strategy of giving chemotherapy and radiation therapy at the same time was becoming a standard approach in many different cancers. This included cancers of the pancreas, of the esophagus, of the head and neck, of the rectum, and so that sort of idea was attempted in lung cancer. Now we weren’t sure if we could actually give chemotherapy and radiation at the same time to somebody who had lung cancer. It’s a bit different radiating the mid-chest area where the heart is going to get radiation, the lungs are exposed to a lot of toxicity from radiation, the esophagus would oftentimes be in the field of radiation. So the first thing we had to do was prove that it was safe and feasible to do, and indeed investigators did demonstrate that. The next step was to determine whether that strategy of giving chemotherapy and radiation at the same time would truly be more effective than giving them separately – there were a lot of theoretical advantages to doing that. First, you would not delay the radiation therapy. Secondly, you might be able to give both therapies at the same time which would work to kill cancer cells in different ways simultaneously, but we knew that it would come at a risk.

We knew that it would come at a risk of increased side effects when you give the treatments together versus giving them separately. Several randomized trials were conducted in the United States, in Japan, in Europe, that looked at comparing the concurrent administration of chemotherapy and radiation to the sequential administration of those two. Those trials by and large demonstrated that while it was more difficult on patients and there were certainly more side effects, you could improve cure rates by giving the treatment concurrently.

So really through the 1990s and into the early 2000s, the standard of care treatment for those who were well enough and fit enough for this type of therapy was to give concurrent chemotherapy and radiation therapy.


GRACE Video

Local Therapy for Limited Acquired Resistance

Share
GRACE Cancer Video Library - Lung

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.

Download Transcript

How Did You Like This Video?

Please feel free to offer comments and raise questions in our Discussion Forums.

 

Transcript

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

GCVL_LU-FB06_Local_Therapy_Limited_AR_02

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.

GCVL_LU-FB06_Local_Therapy_Limited_AR_04

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.

GCVL_LU-FB06_Local_Therapy_Limited_AR_05

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.

GCVL_LU-FB06_Local_Therapy_Limited_AR_06

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.

GCVL_LU-FB06_Local_Therapy_Limited_AR_07

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.

GCVL_LU-FB06_Local_Therapy_Limited_AR_09 

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.

GCVL_LU-FB06_Local_Therapy_Limited_AR_10

[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.

GCVL_LU-FB06_Local_Therapy_Limited_AR_11

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.


Ask Us, Q&A
Lung/Thoracic Cancer Expert Content

Archives

Share

GRACE Cancer Video Library - Lung Cancer Videos

 

2015_Immunotherapy_Forum_Videos

 

2015 Acquired Resistance in Lung Cancer Patient Forum Videos

Share

Join the GRACE Faculty

Breast Cancer Blog
Pancreatic Cancer Blog
Kidney Cancer Blog
Bladder Cancer Blog
Head/Neck Cancer Blog
Share

Subscribe to the GRACEcast Podcast on iTunes

Share

Email Newsletter icon, E-mail Newsletter icon, Email List icon, E-mail List icon

Subscribe to
GRACE Notes
   (Free Newsletter)

Other Resources

Share

ClinicalTrials.gov


Biomedical Learning Institute

peerview_institute_logo_243